Accepted Manuscript Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers Nobumitsu Tominaga, Timi Edeki, James Li, Maria Learoyd, M. René Bouw, Shampa Das, Senior Clinical Pharmacology Scientist PII:
S1341-321X(15)00090-2
DOI:
10.1016/j.jiac.2015.04.006
Reference:
JIC 282
To appear in:
Journal of Infection and Chemotherapy
Received Date: 12 February 2015 Revised Date:
27 March 2015
Accepted Date: 10 April 2015
Please cite this article as: Tominaga N, Edeki T, Li J, Learoyd M, Bouw MR, Das S, Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers, Journal of Infection and Chemotherapy (2015), doi: 10.1016/ j.jiac.2015.04.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Phase I study assessing the safety, tolerability, and
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pharmacokinetics of avibactam and ceftazidime-avibactam
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in healthy Japanese volunteers
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Nobumitsu Tominaga a, Timi Edeki b, James Li c, Maria Learoyd d, M. René Bouw e,
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Shampa Das d *
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a
AstraZeneca, Osaka, Japan
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b
AstraZeneca, Wilmington, DE, USA
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c
AstraZeneca, Waltham, MA, USA
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d
AstraZeneca, Macclesfield, Cheshire, UK
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e
Formerly of AstraZeneca, Mölndal, Sweden
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* Corresponding author: Senior Clinical Pharmacology Scientist, Quantitative Clinical
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Pharmacology, 11G Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG.
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Tel.: +44 1625 230812. E-mail address: [email protected] (Shampa
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Das)
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ACCEPTED MANUSCRIPT ABSTRACT
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Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown to
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restore the in vitro activity of ceftazidime against pathogens producing Ambler class
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A, C, and some class D β-lactamases. This study aimed to evaluate the safety,
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tolerability, and pharmacokinetics of single and repeatedmultiple doses of avibactam
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alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind
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study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were
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randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000
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mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml
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intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3–6, and once on
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Day 7. There were no deaths or serious adverse events. Nine treatment-emergent
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adverse events were reported in three subjects in the avibactam group – including
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one elevation in transaminase levels, and three vital signs events (tachycardia,
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palpitations, and orthostatic hypotension) – and one in the ceftazidime-avibactam
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group. All events were considered mild. After single or repeatedmultiple dosing,
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plasma concentrations of avibactam and ceftazidime declined in a multi-exponential
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manner. No plasma concentration accumulation was observed, and the majority of
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avibactam was excreted unchanged in urine within 24 h. No clinically relevant
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changes in intestinal bacterial flora were observed. In conclusion, avibactam alone
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and ceftazidime-avibactam were generally well tolerated in healthy male Japanese
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subjects, and avibactam pharmacokinetics were comparable whether administered
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alone or in combination with ceftazidime.
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Keywords: avibactam, ceftazidime, Japanese, safety, tolerability, pharmacokinetics
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1. Introduction There is abundant evidence of increasing antimicrobial resistance in the AsiaPacific region, including resistance among species causing complicated intra-
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abdominal infections (cIAI), urinary tract infections (cUTI), or nosocomial pneumonia
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[1–5]. Recent surveillance studies in Japan have also demonstrated an increasing
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incidence of multi-drug resistant bacterial infections [6–10].
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One of the most common mechanisms for antibiotic drug resistance in Gram-
negative organisms is the production of extended spectrum β-lactamases (ESBLs)
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[11,12], although bacteria producing AmpC β-lactamases are also spreading
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[5,13,14]. While carbapenems are still widely used for serious infections caused by
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potentially β-lactamase-producing pathogens [15], the prevalence of pathogens
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producing carbapenemases, particularly Klebsiella pneumoniae serine
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carbapenemases (KPCs), is a growing threat [11,16].
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activity [17–19]. Avibactam restores the in vitro and in vivo activity of ceftazidime
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against organisms producing Ambler class A ESBLs and carbapenemases (including
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KPC), class C, and some class D enzymes [20–23]. Two multinational Phase II trials
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of ceftazidime-avibactam in cUTI and cIAI have been completed [24,25], and it is
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currently undergoing development in a series of multinational Phase III clinical trials
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in patients with cUTI (NCT01595438, NCT01599806), cIAI (NCT01726023,
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NCT01499290, NCT01500239), or nosocomial pneumonia (NCT01808092). Two of
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these studies (NCT01595438 and NCT01808092) include patients enrolled at
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multiple centers in Japan.
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The aim of the present study was to investigate the safety, tolerability and
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pharmacokinetics (PK) of avibactam alone and in combination with ceftazidime
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(ceftazidime-avibactam) after single and repeated intravenous (IV) infusion in healthy 3
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Japanese subjects.
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2. Subjects and methods This was a Phase I, randomized, double-blind, placebo-controlled, parallel-group study (NCT01291602) conducted in healthy Japanese volunteers at a single center
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living in the United States.
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The study was approved by the Institutional Review Board, and was performed
in accordance with the ethical principles of the Declaration of Helsinki, consistent with
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Good Clinical Practice and applicable regulatory requirements, and the AstraZeneca
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policy on Bioethics and Human Biological Samples. All subjects provided written,
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informed consent prior to initiation of the study.
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2.1. Subjects
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Healthy male and female Japanese subjects aged 20–45 years, with a body
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mass index (BMI) of 17–27 kg/m2, were eligible for inclusion in the study if they were
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born in Japan, and both their parents and all grandparents were Japanese. They
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were also required to be in possession of a valid Japanese passport, and to have
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been an expatriate of Japan for no more than 5 years. Female subjects were
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required to be of non-childbearing potential, and male subjects had to be willing to
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use double-barrier contraception from the first dose until 3 months after the last dose
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of study drug.
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Subjects were excluded from the study if they had any condition requiring regular
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medication, had used (within the 14 days prior to first dose of study drug) any
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medication known to cause PK drug interaction, or had (within the past 30 days)
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received any other new compound or participated in another clinical study. Other
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exclusion criteria included cardiac abnormalities such as prolonged or shortened QT
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interval (corrected using Fridericia’s formula, QTcF), left or (complete) right bundle
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branch block, Wolff-Parkinson-White syndrome, blood pressure >140/90 mmHg,
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resting heart rate 85 beats per minute (bpm), or family history of unexplained 5
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>5 cigarettes/day, drank >5 cups of coffee/day, or exceeded 21 units of alcohol per
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week were also excluded. Consumption of grapefruit-containing products was not
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permitted from 7 days prior to the first study dose.
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2.2. Treatment
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Eligible subjects were randomized in a 2:2:1 ratio to receive either avibactam
500 mg, or ceftazidime 2000 mg plus avibactam 500 mg, or placebo (0.9% saline),
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each administered as a 100 ml infusion over 2 h.
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Study drug was administered once on Day 1, every 8 h (6 am to 8 am, 2 pm to 4
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pm, and 10 pm to 12 pm) on Days 3–6, and once on Day 7, with a follow-up visit 3–5
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days after the last dosing day. No doses were administered on Day 2. Morning doses
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were administered after an overnight fast of at least 10 h. On Days 3–6, subjects
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fasted for 1 h before and after the second and third doses. Water was permitted
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throughout, as required by subjects.
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No concomitant medication, other than paracetamol (acetaminophen), was allowed without the consent of the investigator. Any paracetamol given had to be
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prescribed by the investigator, and the AstraZeneca Study Team Physician was
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informed.
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Each individual was assigned a unique randomization code using the global
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randomization scheme. The investigator and subjects were blinded to the treatments
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being administered; however, blinding could be broken in the case of a medical
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emergency or unexpected serious adverse event (SAE).
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2.3. Objectives
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The primary objective of the study was to investigate the safety and tolerability of avibactam, alone or in combination with ceftazidime, administered as single and
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were to investigate in healthy Japanese subjects the PK of avibactam, alone and in
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combination with ceftazidime, and the influence of avibactam, alone and in
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combination with ceftazidime, on intestinal bacterial flora.
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2.4. Safety and tolerability
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The safety population was defined as all subjects who received at least one dose of randomized study compound (avibactam, ceftazidime-avibactam, or placebo) and
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for whom any post-dose data were available.
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Safety and tolerability were assessed by evaluation of treatment-emergent adverse events (TEAEs) (defined as those occurring or worsening after the first dose
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of, but not necessarily related to, study compound), SAEs, other significant adverse
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events (OAEs), physical examination, vital signs, electrocardiograms (ECGs), and
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clinical laboratory tests. TEAEs were coded using MedDRA version 12.0 or higher,
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and causal relationship between investigational product and each TEAE was
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assessed by the investigator. Vital signs were measured at regular intervals on Days
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1–7, and 12-lead ECGs were performed pre-dose and then at regular intervals on
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Days 1, 3, and 7, and once (pre-dose) on Days 4, 5, and 6.
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2.5. Pharmacokinetics
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The PK population was defined as all subjects who received at least one dose of
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study compound, completed the study without any major protocol violation, and
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provided evaluable data for the PK analyses.
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Blood samples were collected pre-dose and for 24 h after the start of dosing (at
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0.5, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 4, 6, 8, 12, and 24 h) on Day 1 and Day 7, and pre-
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dose, 2 and 4 h after the start of the morning infusion on Day 3 and Day 5. Urine
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samples were collected on Days 1, 3, and 7 pre-dose then during the periods 0–8 h,
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8–16 h, and 16–24 h. 7
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Ceftazidime and avibactam concentrations in plasma and urine were analyzed by Quotient Bioresearch (Fordham, Cambs., UK) as described previously [26].
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Briefly, prepared plasma and urine samples of each drug were analyzed using ultra-
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performance liquid chromatography and pneumatic-assisted electrospray
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(TurboIonSpray™, AB SCIEX, Concord, Ontario, Canada) tandem mass
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spectrometry.
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Avibactam concentrations in plasma were assessed over the validated
calibration ranges 10–1,000 ng/ml (low range) and 500–50,000 ng/ml (high range) in
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human plasma, with a validated dilution of 10-fold with human plasma. The lower
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limit of quantification (LLOQ) was previously established as 10 and 500 ng/ml,
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respectively, during the method validation. Comparing quality control (QC) samples,
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the between-assay precision (% coefficient of variation [CV]) ranged from 3.0–5.4%
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and 0.3–6.5% for the avibactam high and low calibration range, respectively.
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validated calibration ranges 87.4–2,620 ng/ml and 100–5,000 ng/ml in human urine,
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respectively, with a validated dilution of 5,000-fold with human urine. The LLOQ for
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ceftazidime was established as 87.4 ng/ml during the method validation. The
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between-assay precision (%CV) for the ceftazidime and avibactam assay ranged
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from 4.9–8.4% and 2.6–5.9%, respectively.
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Data collection and peak integration were performed using Analyst software
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(version 1.4.2 and 1.5.1). Standard regression and quantitation were performed using
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Watson LIMS (version 7.2).
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Plasma PK parameters for avibactam and ceftazidime were determined on Day 1 (single-dose) and Day 7 (multiple-dose), including: Single-dose parameters: maximum concentration (Cmax), time of maximum concentration (tmax), area under the curve (AUC) from time 0 to infinity (AUC), 8
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elimination half-life (t½), volume of distribution at steady state (Vss), and clearance
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(CL). Multiple-dose parameters: Cmax at steady state (Cmax ss), tmax at steady state, AUC
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during the dosing interval at steady state (AUCτ), t½ at steady state, Vss, CL at steady
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state, accumulation ratio for Cmax, calculated as Cmax ss Day 7/Cmax Day 1,
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accumulation ratio for AUC, calculated as AUCτ Day 7/AUCτ Day 1, temporal
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change parameter (TCP), calculated as AUCτ Day 7/AUC Day 1.
The amount of drug excreted unchanged in urine (Ae), the fraction of the dose
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excreted in urine (Fe) and renal CL were also determined for avibactam and
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ceftazidime.
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The PK results reported below focus on avibactam as the novel entity in the study, but PK data for ceftazidime are included in the tables and figure.
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2.6. Intestinal bacterial flora
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Fecal samples were collected for analysis of intestinal bacterial flora on Day –1, Days 5 and 8, and at the follow-up visit. Aerobic and anaerobic bacteria were
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identified, quantitated and evaluated for change from baseline analysis.
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2.7. Statistical analysis
No formal statistical hypothesis testing was performed. The aim was to enroll 15
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subjects overall. Missing data were excluded from all analyses (i.e., there was no
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imputation of data), and any extreme values relative to the majority of data were
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included.
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Continuous safety variables were summarized using descriptive statistics, and
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adverse events (AEs) summarized by treatment group. Clinical laboratory test values
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were presented for each subject, with abnormal values flagged. Plasma and urine PK
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parameters for avibactam and ceftazidime were summarized using descriptive 9
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intestinal bacterial flora were presented using descriptive statistics.
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3. Results The study was conducted between 17 February and 8 April 2011. Sixteen
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subjects (all male) were enrolled in the study and randomized. All subjects except
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one completed the study. One subject randomized to ceftazidime-avibactam
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withdrew consent after the morning dose on Day 3, but data obtained up to that point
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were used in the safety and PK analyses. Baseline characteristics of all subjects are
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shown in Table 1. Mean age in subjects in the placebo group was older than in
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subjects in the avibactam and ceftazidime-avibactam groups, and mean weight and
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BMI varied somewhat across the treatment groups. None of these differences were
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expected to impact the overall interpretation of safety and PK data.
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3.1. Safety
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There were no deaths, SAEs, or TEAEs that led to discontinuation from the study during single- or repeatedmultiple-dose administration of avibactam or
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ceftazidime-avibactam. During the single-dose period of avibactam alone, one TEAE
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(tachycardia) was reported (Table 2). During repeatedmultiple-dose administration,
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seven TEAEs were reported by two subjects in the avibactam group (palpitations,
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chest discomfort, infusion site reactions, dyspnoea, contact dermatitis, and increased
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transaminases) and one TEAE (orthostatic hypotension) was reported in a subject in
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the ceftazidime-avibactam group (Table 2). All TEAEs except contact dermatitis were
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considered related to study compound, and all were considered mild in severity.
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There was only one clinically significant change in laboratory values (reported as
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an OAE), a mild increase in transaminase levels during the repeatedmultiple-dosing
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phase in a 41-year old subject in the avibactam group: alanine aminotransferase
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(ALT), aspartate aminotransferase (AST), gamma glutamyl-transpeptidase (GGT)
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and alkaline phosphatase (AP) increased above the reference ranges between Day 2
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and Day 8, while total bilirubin remained within the reference range throughout the
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allergies. He remained asymptomatic, and all other laboratory test results were within
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clinically acceptable limits. Although his transaminase levels had not normalized by
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the end of the study, most liver-related test values were decreasing at the follow-up
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visit 3 days after the last dose of study drug (ALT 307 U/l, AST 86 U/l, GGT 145 U/l,
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AP 171 U/l, total bilirubin 0.6 mg/dl). The subject was lost to follow-up thereafter.
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Two subjects in the ceftazidime-avibactam group had minor increases in liver
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enzymes: one had minor elevations in ALT on Day 8 and at follow-up (67 and 77 U/l,
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respectively), and in AST at follow-up (48 U/l); the other had a mild elevation in ALT
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at follow-up (80 U/l), and raised total bilirubin on Days 2 and 8 (1.4 and 1.5 mg/dl,
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respectively).
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There were no clinically significant abnormalities in ECG data at any time point, no AEs related to ECG measurements and no clinically significant findings on
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physical examination.
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3.2. Pharmacokinetic analysis
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Fig. 1 shows the geometric mean plasma avibactam concentration–time curves (log scale) for avibactam and ceftazidime-avibactam following single-dose (Day 1)
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and repeatedmultiple-dose (Day 7) administration. The plasma Cmax of both
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avibactam and ceftazidime was achieved at the end of the IV infusion, after which
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plasma concentrations declined in a multi-exponential manner.
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Plasma PK parameters for avibactam and ceftazidime are summarized in Table
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3 (single-dose, Day 1) and Table 4 (repeatedmultiple-dose, Day 7). The mean half-
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life of avibactam was 1.4 h following single or multiple doses alone or in combination
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with ceftazidime. No plasma accumulation was observed for avibactam or
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ceftazidime after repeatedmultiple-dose administration. The trough concentrations
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were comparable for study Days 5 and 7 (data not shownFig. 2) and accumulation 12
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ratios for AUCτ (RacAUC) were approximately 1 (Table 4). The majority of avibactam was excreted unchanged in the urine within 24 h (Table 5). Following single-dose administration on Day 1, the mean percentage of
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avibactam excreted in urine was 73.2% for avibactam alone and 86.5% when given
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in combination with ceftazidime. Following multiple-dose administration, the mean
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percentage of the avibactam dose excreted in urine on Day 7 was 99.5% for
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avibactam alone, and 95.8% when given in combination with ceftazidime. Avibactam
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mean renal CL when given alone and in combination with ceftazidime was
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approximately 8.8 l/h (±standard definitiondeviation [SD] 4.03 l/h) and 9.5 l/h (±SD
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1.658 l/h), respectively, similar to the total plasma CL for avibactam (Tables 3 and 4),
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showing that avibactam is predominantly renally excreted in Japanese subjects.
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The results indicate that the PK of avibactam were not altered when administered in the presence of ceftazidime following either single or multiple daily
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doses in Japanese subjects, that the PK of ceftazidime were comparable following
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single and multiple dosing in the presence of avibactam, and that the majority of both
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avibactam and ceftazidime is excreted unchanged.
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3.3. Intestinal bacterial flora
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There were no clinically relevant trends observed for changes in intestinal bacterial flora with avibactam alone.
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With ceftazidime-avibactam, slight increases were observed in two aerobic
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species (Lactobacillus spp. and Enterococcus faecalis) Days 5–Day 10 and two
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anaerobic species (Peptostreptococcus spp, from Days 5–Day 10 and
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Bifidobacterium spp.) Days 5–Day 8 (Table 6), but these were not considered
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clinically relevant, and there was no associated AE of diarrhea.
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4. Discussion The safety and pharmacokinetics of ceftazidime-avibactam have not been
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investigated previously in Japanese subjects. Safety and tolerability findings in this
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study were similar to those seen in studies that included healthy White, Black, African
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and Asian subjects (NCT01395420; NCT01430910; NCT01534247) [27–31], with no
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new safety concerns being identified. One individual in this study had changes in liver
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function parameters during treatment with avibactam that were potentially clinically
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significant, but there were no associated clinical safety concerns, and no reported
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transaminase elevations in any other subjects treated with avibactam or ceftazidime-
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avibactam in this study, nor in other studies carried out to date [24,25,27–31].
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As in the present study, previous investigations in non-Japanese subjects
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showed no evidence of drug–drug interaction between ceftazidime and avibactam,
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with comparable PK of both agents after single and multiple dosing, and no obvious
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accumulation of either component [27]. Similarly, CL of avibactam and ceftazidime
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has been shown to be predominantly renal in both the small cohort of Japanese
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subjects in the present study and in non-Japanese subjects investigated previously,
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with the majority of both drugs excreted unchanged in urine [28,29]. In those studies,
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avibactam AUC and t½ were similar. In single- and multiple-ascending dose studies in
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healthy male (non-Japanese) volunteers, avibactam pharmacokinetics were shown to
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be linear, with dose-proportional increase in exposure [29]. Ceftazidime exposure
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was lower in non-Japanese subjects [28–30] compared with Japanese subjects in the
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present study. The small increase in ceftazidime exposure observed in the present
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study was not considered to have an impact on the dose recommendation for
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ceftazidime-avibactam in Japanese patients.
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Analysis of microbiological data from the current study, in addition to the absence of any AE of diarrhea, suggests there may be no clinically significant
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changes in intestinal bacterial flora with ceftazidime and avibactam. The dosage regimen chosen for this study (ceftazidime 2000 mg plus avibactam 500 mg) reflects that currently under investigation in ongoing Phase III studies, and
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was based on the results of in vitro susceptibility testing, hollow fiber experiments
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and preclinical data [20,32–34], first-in-man studies in healthy Western subjects,
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which demonstrated an acceptable safety and tolerability profile [29] and a Phase II
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study in cIAI [24].
Despite inclusion criteria allowing the enrollment of females, none participated in
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this study. However, a previous study in healthy American subjects in the U.S.A.
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indicated that there were no significant gender differences in terms of avibactam PK
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[31].
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While the clinical trial program is ongoing, on 25 February 2015, the U.S. Food and Drug Administration gave approval, based on data from the Phase II program,
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for the use of ceftazidime-avibactam in the treatment of adults with cIAI, in
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combination with metronidazole, or cUTI including kidney infections (pyelonephritis),
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who have limited or no alternative treatment options [35]. In conclusion, avibactam alone and ceftazidime-avibactam were generally well
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tolerated at the doses tested when administered as single and multiple doses in
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healthy male Japanese subjects. There were no deaths, SAEs, or clinically significant
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ECG changes. The PK of avibactam and ceftazidime following either single or
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multiple daily doses were comparable whether administered alone or in combination,
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and there was no plasma accumulation of either drug. Overall, these findings indicate
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that ceftazidime-avibactam exposure and tolerability are comparable in Japanese
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and non-Japanese subjects, and support the future evaluation of ceftazidime-
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avibactam in clinical trials in Japanese patients.
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Conflict of interest N. Tominaga, T. Edeki, J. Li, S. Das and M. Learoyd are employees of AstraZeneca. M.R. Bouw was an employee of AstraZeneca at the time the study was
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carried out and during the development of the manuscript.
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Acknowledgments
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The authors would like to thank Mark Yen, MD, California Clinical Trials, Glendale, CA, USA, the Principal Investigator for the study. This study was
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sponsored by AstraZeneca.
Medical writing support was provided by Liz Anfield and Catherine Savage of
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Prime Medica Ltd, Knutsford, Cheshire and funded by AstraZeneca. The design and
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conduct of the study, as well as analysis of the study data and opinions, conclusions,
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and interpretation of the data, are the responsibility of the authors.
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2011;63:114-23.
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[2] Liu YM, Chen YS, Toh HS, Huang CC, Lee YL, Ho CM, et al. In vitro
susceptibilities of non-Enterobacteriaceae isolates from patients with intra-
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abdominal infections in the Asia-Pacific region from 2003 to 2010: results
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from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J
345
Antimicrob Agents 2012;40 Suppl:S11-S17.
M AN U
346
SC
342
[3] Lu PL, Liu YC, Toh HS, Lee YL, Liu YM, Ho CM, et al. Epidemiology and antimicrobial susceptibility profiles of Gram-negative bacteria causing urinary
348
tract infections in the Asia-Pacific region: 2009-2010 results from the Study
349
for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob
350
Agents 2012;40 Suppl:S37-S43.
[4] Rosenthal VD, Bijie H, Maki DG, Mehta Y, Apisarnthanarak A, Medeiros EA,
EP
351
TE D
347
et al. International Nosocomial Infection Control Consortium (INICC) report,
353
data summary of 36 countries, for 2004-2009. Am J Infect Control
354
355 356
AC C
352
2012;40:396-407.
[5] Sheng WH, Badal RE, Hsueh PR. Distribution of extended-spectrum blactamases, AmpC b-lactamases, and carbapenemases among
357
Enterobacteriaceae isolates causing intra-abdominal infections in the Asia-
358
Pacific region: results of the study for Monitoring Antimicrobial Resistance
359
Trends (SMART). Antimicrob Agents Chemother 2013;57:2981-8.
17
ACCEPTED MANUSCRIPT 360
[6] Fujiwara M, Mizunaga S, Nomura N, Mitsuyama J, Hashido H, Yamaoka K, et
361
al. [Sensitivity surveillance of Pseudomonas aeruginosa isolates for several
362
antibacterial agents in Gifu and Aichi prefecture (2008)]. Jpn J Antibiot
363
2012;65:15-26. [7] Kuroda H, Yano H, Hirakata Y, Arai K, Endo S, Kanamori H, et al. Molecular
RI PT
364
characteristics of extended-spectrum b-lactamase-producing Escherichia coli
366
in Japan: emergence of CTX-M-15-producing E. coli ST131. Diagn Microbiol
367
Infect Dis 2012;74:201-3.
368
SC
365
[8] Izumida M, Nagai M, Ohta A, Hashimoto S, Kawado M, Murakami Y, et al. Epidemics of drug-resistant bacterial infections observed in infectious disease
370
surveillance in Japan, 2001-2005. J Epidemiol 2007;17 Suppl:S42-S47.
371
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[9] Nakano R, Nakano A, Abe M, Inoue M, Okamoto R. Regional outbreak of CTX-M-2 b-lactamase-producing Proteus mirabilis in Japan. J Med Microbiol
373
2012;61:1727-35.
374
TE D
372
[10] Watanabe A, Yanagihara K, Matsumoto T, Kohno S, Aoki N, Oguri T, et al. Nationwide surveillance of bacterial respiratory pathogens conducted by the
376
Surveillance Committee of Japanese Society of Chemotherapy, Japanese
377
Association for Infectious Diseases, and Japanese Society for Clinical
379
380 381
382
AC C
378
EP
375
Microbiology in 2009: general view of the pathogens' antibacterial susceptibility. J Infect Chemother 2012;18:609-20.
[11] Bush K. Proliferation and significance of clinically relevant b-lactamases. Ann N Y Acad Sci 2013;1277:84-90. [12] Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against
383
resistant gram-negative organisms: extended-spectrum b-lactamase-
384
producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, 18
ACCEPTED MANUSCRIPT 385
and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc
386
2011;86:250-9.
387
[13] Gutkind GO, Di CJ, Power P, Radice M. b-lactamase-mediated resistance: a biochemical, epidemiological and genetic overview. Curr Pharm Des
389
2013;19:164-208.
390
RI PT
388
[14] Matsumura Y, Yamamoto M, Higuchi T, Komori T, Tsuboi F, Hayashi A, et al. Prevalence of plasmid-mediated AmpC b-lactamase-producing Escherichia
392
coli and spread of the ST131 clone among extended-spectrum b-lactamase-
393
producing E. coli in Japan. Int J Antimicrob Agents 2012;40:158-62.
M AN U
394
SC
391
[15] Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to
396
Enterobacteriaceae producing extended-spectrum b-lactamases: a
397
systematic review and meta-analysis. J Antimicrob Chemother 2012;67:2793-
398
803.
401 402 403
404
Enterobacteriaceae. Emerg Infect Dis 2011;17:1791-8.
EP
400
[16] Nordmann P, Naas T, Poirel L. Global spread of Carbapenemase-producing
[17] Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, et al. Avibactam is a covalent, reversible, non-b-lactam b-lactamase inhibitor. Proc Natl Acad Sci U
AC C
399
TE D
395
S A 2012;109:11663-8.
[18] Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De LF, Sanyal G, et al.
405
Structural insight into potent broad-spectrum inhibition with reversible
406
recyclization mechanism: avibactam in complex with CTX-M-15 and
407
Pseudomonas aeruginosa AmpC b-lactamases. Antimicrob Agents
408
Chemother 2013;57:2496-505.
19
ACCEPTED MANUSCRIPT 409
[19] Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagace-Wiens
410
PR, et al. Ceftazidime-avibactam: a novel cephalosporin/b-lactamase inhibitor
411
combination. Drugs 2013;73:159-77.
412
[20] Endimiani A, Hujer KM, Hujer AM, Pulse ME, Weiss WJ, Bonomo RA. Evaluation of ceftazidime and NXL104 in two murine models of infection due
414
to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother
415
2011;55:82-5.
[21] Lagace-Wiens PR, Tailor F, Simner P, DeCorby M, Karlowsky JA, Walkty A,
SC
416
RI PT
413
et al. Activity of NXL104 in combination with b-lactams against genetically
418
characterized Escherichia coli and Klebsiella pneumoniae isolates producing
419
class A extended-spectrum b-lactamases and class C b-lactamases.
420
Antimicrob Agents Chemother 2011;55:2434-7.
421
M AN U
417
[22] Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against
423
carbapenemase-producing Enterobacteriaceae. Antimicrob Agents
424
Chemother 2011;55:390-4.
EP
TE D
422
[23] Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C,
426
et al. In vitro activity of the b-lactamase inhibitor NXL104 against KPC-2
427 428
AC C
425
carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 2009;64:326-9.
429
[24] Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of
430
the efficacy and safety of ceftazidime/avibactam plus metronidazole versus
431
meropenem in the treatment of complicated intra-abdominal infections in
432
hospitalized adults: results of a randomized, double-blind, Phase II trial. J
433
Antimicrob Chemother 2013;68:1183-92.
20
ACCEPTED MANUSCRIPT [25] Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka
435
J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-
436
cilastatin in the treatment of complicated urinary tract infections, including
437
acute pyelonephritis, in hospitalized adults: results of a prospective,
438
investigator-blinded, randomized study. Curr Med Res Opin 2012;28:1921-31.
439
RI PT
434
[26] Das S, Armstrong J, Mathews D, Li J, Edeki T. Randomized, placebo-
controlled study to assess the impact on QT/QTc interval of supratherapeutic
441
doses of ceftazidime-avibactam or ceftaroline fosamil-avibactam. J Clin
442
Pharmacol 2014;54:331-40.
[27] Edeki T, Armstrong J, Li J.Pharmacokinetics of avibactam (AVI) and
M AN U
443
SC
440
ceftazidime (CAZ) following separate or combined administration in healthy
445
volunteers. 53rd International Conference on Antimicrobial Agents and
446
Chemotherapy (ICAAC), September 10-13, 2013, Denver, CO, USA (Abstract
447
A-1019).
448
TE D
444
[28] Li J, Armstrong J, Edeki T.Pharmacokinetic (PK) drug interaction study of ceftazidime-avibactam (CAZ-AVI) and metronidazole (MTZ) in healthy
450
volunteers. Poster presented at the 53rd International Conference on
451
Antimicrobial Agents and Chemotherapy (ICAAC), September 10-13, 2013,
452
Denver, CO, USA.
454
AC C
453
EP
449
[29] Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with
455
ceftazidime in healthy male volunteers: results of two randomized, placebo-
456
controlled studies. Clin Drug Invest 2015;In press.
457 458
[30] Nicolau DP, Siew L, Armstrong J, Edeki T, Bouw R.Concentration of avibactam (AVI) and ceftazidime (CAZ) in plasma and epithelial lining fluid
21
ACCEPTED MANUSCRIPT 459
(ELF) in healthy volunteers. International Conference on Antimicrobial Agents
460
and Chemotherapy (ICAAC), September 10-13, 2013, Denver, CO, USA
461
(Abstract A-1027).
462
[31] Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. Clin Ther 2015;Mar 10 (epub ahead
464
of print).
465
RI PT
463
[32] Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in
combination with b-lactams against Klebsiella pneumoniae isolates producing
467
KPC carbapenemases. Antimicrob Agents Chemother 2009;53:3599-601.
M AN U
SC
466
[33] Levasseur P, Girard AM, Miossec C, Pace J, Coleman K. In vitro antibacterial
469
activity of the ceftazidime-avibactam combination against Enterobacteriaceae,
470
including strains with well-characterized beta-lactamases. Antimicrob Agents
471
Chemother 2015;59:1931-4.
TE D
468
[34] Coleman K, Levasseur P, Girard AM, Borgonovi M, Miossec C, Merdjan H, et
473
al. Activities of ceftazidime and avibactam against beta-lactamase-producing
474
Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob
475
Agents Chemother 2014;58:3366-72.
477 478 479
[35]
AVYCAZ Prescribing Information. 2015;Available at:
AC C
476
EP
472
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494lbl.pdf. Accessed 16 March 2015.
480
22
ACCEPTED MANUSCRIPT 481
Table 1
482
Subject demographics (safety population).
Ceftazidimeavibactam
Placebo
(n = 6)
(n = 7)
(n = 3)
(n = 16)
Age, years
28.8 (6.7)
25.4 (3.3)
36.7 (9.3)
28.8 (7.0)
Male, n (%)
6 (100)
7 (100)
3 (100)
16 (100)
Height, cm
175.2 (4.8)
170.7 (3.5)
174.3 (6.7)
173.1 (4.8)
Weight, kg
73.3 (9.9)
63.3 (4.6)
78.3 (7.4)
69.9 (9.4)
2
24.0 (2.2)
21.9 (1.6)
25.7 (0.6)
23.4 (2.2)
SC
M AN U
BMI, kg/m
BMI: body mass index.
484
Data are mean (standard deviation), unless otherwise stated.
AC C
EP
TE D
483
All subjects
RI PT
Avibactam
23
ACCEPTED MANUSCRIPT 485
Table 2
486
TEAEsa regardless of perceived relationship to study drug (safety population).
Ceftazidimeavibactam
(n = 6)
(n = 7)
(n = 3)
1
0
0
b
1
0
0
2
1
0
c
0
0
c
0
0
d
0
0
d
0
0
d
0
0
c
0
0
M AN U
Tachycardia
SC
Single-dose period
Any AE n
RepeatedMultiple-dose period
Any AE, n
1
Chest discomfort
TE D
Palpitations
1
1
Infusion site thrombosis
1
EP
Infusion site extravasation
AC C
Transaminases increased
Placebo
RI PT
Avibactam alone
1
Dyspnoea
1
Contact dermatitis
1
c
0
0
Orthostatic hypotension
0
1
0
487
a
488
study medication; AE counts are at the subject level; preferred term counts are at the event level;
489
c
490
AE: adverse event; TEAE: treatment-emergent adverse events.
All AEs were considered to be mild and all except contact dermatitis were considered to be related to b
d
Occurred in the same individual; Occurred in the same individual.
24
ACCEPTED MANUSCRIPT Table 3
492
Single-dose avibactam and ceftazidime plasma PK parameters on Day 1a following
493
treatment with avibactam 500 mg alone or avibactam 500 mg plus ceftazidime 2000
494
mg (PK population)
Avibactam
(avibactam alone
(ceftazidime-
group)
avibactam group)
PK parameter
n=6
n=7
b
2.0 (2.0, 2.0)
2.0 (2.0, 2.0)
2.0 (2.0, 2.1)
Cmax (µg/ml)
15.1 (9.2)
15.9 (13.6)
110.0 (13.9)
AUC
43.1 (12.3)
45.5 (12.2)
354.0 (13.0)
1.4 (0.1)
1.7 (0.2)
18.3 (15.3)
12.4 (14.0)
11.0 (12.2)
5.6 (13.0)
c
Vss (l)
CL (l/h)
1.4 (0.1)
19.7 (16.2)
TE D
t½ (h)
11.6 (12.3)
Ceftazidime
(ceftazidime-avibactam group) n=7
SC
tmax (h)
RI PT
Avibactam
M AN U
491
a
Values are geometric mean (coefficient of variation [%]) unless stated otherwise; Median (range);
496
c
Mean (standard deviation).
497
AUC: area under the curve; CL: clearance; Cmax, maximum concentration; PK: pharmacokinetic; t½,
498
terminal elimination half-life; tmax, time of maximum concentration; Vss: volume of distribution at steady
499
state.
AC C
500
b
EP
495
25
ACCEPTED MANUSCRIPT Table 4
502
Multiple-dose avibactam and ceftazidime plasma PK parameters on Day 7a after
503
treatment with avibactam 500 mg alone or avibactam 500 mg plus ceftazidime 2000
504
mg, administered once on Day 1, every 8 h on Days 3 to 6, and once on Day 7 (PK
505
population)
Avibactam
(avibactam alone
(ceftazidime-
group)
avibactam group) b
Ceftazidime
(ceftazidime-avibactam group)
SC
Avibactam
RI PT
501
n=6
n=6
Cmax,ss (µg/ml)
14.8 (11.8)
15.0 (20.6)
113.0 (15.3)
AUCτ (µg·h/ml)
41.5 (9.6)
42.2 (14.4)
348.2 (17.2)
c
1.4 (0.2)
1.4 (0.1)
1.7 (0.1)
11.9 (14.4)
5.7 (17.2)
1.0 (8.3)
0.9 (12.4)
1.0 (12.5)
1.0 (6.8)
0.9 (7.8)
1.0 (8.5)
0.9 (8.1)
1.0 (9.6)
t½,ss (h)
RacAUC
TCP
EP
RacCmax
12.1 (9.6)
TE D
CLss (l/h)
M AN U
PK parameter
1.0 (6.5)
b
n=6
506
a
b
507
were unavailable for one subject in the ceftazidime-avibactam group who withdrew consent and
508
discontinued after Day 3 dosing; Mean (standard deviation).
509
AUCτ: AUC during the dosing interval from 0–8 h; CLss: clearance at steady state; Cmax,ss: maximum
510
concentration at steady state; PK: pharmacokinetic; RacAUC: accumulation ratio for AUCτ, calculated as
511
AUCτ Day 7/AUCτ Day 1; RacCmax: accumulation ratio for Cmax, calculated as Cmax ss Day 7/Cmax Day 1;
512
t½ ss: terminal elimination half-life at steady state; tmax,ss: time of maximum concentration at steady state;
513
TCP: temporal change parameter, calculated as AUCτ Day 7/AUC Day 1.
AC C
Values are geometric mean (geometric coefficient of variation [%]) unless stated otherwise; Data
c
514
26
ACCEPTED MANUSCRIPT Table 5
516
Single- and multiple-dose avibactam and ceftazidime urine pharmacokinetic
517
parameters for cumulative 24-h intervala after treatment with avibactam 500 mg alone
518
or avibactam 500 mg plus ceftazidime 2000 mg, administered once on Day 1, every
519
8 h on Days 3 to 6, and once on Day 7 (PK population).
PK parameter
RI PT
515
Ae (mg)
Fe (%)
Day 1
366 (147.0)
73.2 (29.5)
8.82 (4.03)
Day 3
1,220 (287.0)
81.4 (19.1)
NQ
Day 7
498 (27.1)
99.5 (5.4)
NQ
432 (65.4)
86.5 (13.1)
9.53 (1.58)
1,180 (132.0)
78.9 (8.8)
NQ
479 (64.5)
95.8 (12.9)
NQ
Day 1
1,800 (245.0)
90.1 (12.2)
5.82 (0.82)
Day 3
4,530 (392.0)
76.5 (6.5)
NQ
Day 7
1,930 (84.1)
96.5 (4.2)
NQ
M AN U
alone group), n = 6
b
Day 3
AC C
Day 7
EP
Day 1
TE D
Avibactam (ceftazidimeavibactam group), n = 7
SC
Avibactam (avibactam
CLR (L/h)
Ceftazidime (ceftazidimeb
avibactam group), n = 7
27
ACCEPTED MANUSCRIPT a
Values are arithmetic mean (standard deviation).
521
b
n = 6 for Day 3 and Day 7 because data were unavailable for one subject in the ceftazidime-avibactam
522
group (discontinued after Day 3 dosing).
523
Ae: cumulative amount excreted; CLR: renal clearance; Fe: percentage of
524
cumulated urinary recovery; NQ: non-quantifiable; PK: pharmacokinetic.
AC C
EP
TE D
M AN U
SC
RI PT
520
28
ACCEPTED MANUSCRIPT
RI PT
Table 6 Mean (SD) change from baseline in intestinal flora during treatment with avibactam 500 mg alone, avibactam 500 mg plus ceftazidime 2000
SC
mg, or placebo, administered once on Day 1, every 8 h on Days 3–6, and once on Day 7: log (observed/baseline ratio) (safety population)
Organism
Ceftazidime-avibactam (n = 7)
Day 8
Day 10
Day 5
Day 8
Day 10
Day 5
Day 8
Day 10
3
5
2
3
4
3
2
1
1
–3.96
–8.13
a
TE D
–0.35 (1.63)
–2.42 (1.96) –5.76 (0.59)
Candida spp.
Mean (SD)
1
–1.35
2
1
AC C
n
EP
Mean (SD)
Placebo (n = 3)
Day 5
Baccilus spp.
n
M AN U
Avibactam alone (n = 6)
–1.78 (0.04)
–0.32
–2.77 (5.60) –3.39 (4.18)
0
–2.91 (2.52) –5.22 (6.47)
0
1
–2.11
Enterococcus avium
29
ACCEPTED MANUSCRIPT
Mean (SD)
1
1
1
2.04
1.16
0.06
1
1
1
1
–1.61
0.61
1.70
–0.13
1
1
RI PT
n
Mean (SD)
n
0
5.65
Escherichia coli
Mean (SD)
2
–0.56 (1.36)
3
4
AC C
n
4.85 (3.15)
1
1.75
1.90
1
0
0
6.21
0
0
13.12
EP
Mean (SD)
TE D
Enterococcus faecium
2
M AN U
n
SC
Enterococcus faecalis
1
–4.99 (4.28) –3.03 (5.42)
1
3
3
3
–5.86
0.86 (3.82)
0.90 (1.88)
1.39 (2.30)
30
ACCEPTED MANUSCRIPT
RI PT
Klebsiella pneumoniae
n
3
2
0.26 (2.06)
0.54 (1.70)
1.72 (1.18)
2
2
2
Mean (SD)
–1.61 (4.43)
Streptococcus, viridans group
n
5
–3.18 (2.15) –1.92 (2.71)
AC C
n
1.71
EP
Staphylococcus aureus
1
TE D
Mean (SD)
4
M AN U
Lactobacillus spp.
n
1
1
6.69
2.05
7.59
1
1
1
6.28
–0.46
1.15
0
1
1
–1.14
2.4
1
1
SC
Mean (SD)
1
4
5
0
0
31
ACCEPTED MANUSCRIPT
–1.70 (1.49)
–0.54 (1.38) –0.10 (2.57)
Bacteroides fragilis
6
6
3
0.50 (7.59)
0.57 (2.03)
1.36 (5.33)
3
2
3
–5.26 (2.68)
–1.33 (0.43)
0.02 (3.46)
6
6
–1.07 (7.06)
0.34 (3.85)
Mean (SD)
Clostridium spp.
5
AC C
Mean (SD)
EP
Bifidobacterium spp.
n
5
3
3
3
1.22 (9.68)
1.82 (5.46)
1.50 (3.59)
0.82 (3.38)
–0.08 (2.83)
–0.36 (0.85)
1
1
1
1
3.49
2.51
4.45
0.92
1
1
3
3
3
–1.43
5.05
–2.97 (12.04)
0.58 (1.45)
2.29 (1.84)
TE D
Bacteroides spp.
n
0.22
3
M AN U
Mean (SD)
6
0.51 (1.53)
SC
group
n
1.74
RI PT
Mean (SD)
32
ACCEPTED MANUSCRIPT
Mean (SD)
5
4
4
1
–0.26 (1.98)
–0.25 (3.17)
1.19 (7.01)
–2.94
2
2
2
0.37 (8.33)
0.42 (0.01)
2.31 (4.12)
Mean (SD)
Peptostreptococcus
n
0
0
3
3
3
2.94 (1.19)
4.11 (3.17)
4.06 (8.06)
1
–1.04
1
1
–1.95
6.06
0
EP
Mean (SD)
TE D
spp.
0
M AN U
n
0
SC
Fusobacterium spp.
0
RI PT
n
AC C
Values are mean (SD) natural logarithm (observed/baseline) CFU/g, except where only one patient, individual value is shown and SD is not applicable. Where n = 0, the ratio of that organism in that treatment group is equal to 1. Where n value is missing, there is no ratio for that organism in that treatment group. a
Not anthracis.
CFU: colony forming unit; SD: standard deviation.
33
ACCEPTED MANUSCRIPT Fig. 1. Geometric mean (± SD) plasma concentration–time curves following singledose administration (Day 1) and multiple-dose administration every 8 h (Day 7) administration of (a) avibactam 500 mg (alone or as ceftazidime-avibactam) and (b) ceftazidime 2000 mg (administered as ceftazidime-avibactam) (semi-log scale) (PK
RI PT
population). Fig. 2. Geometric mean (± SD) trough plasma concentration–time data on Days 5 and 7 for (a) avibactam 500 mg (alone or as ceftazidime-avibactam) and
AC C
EP
TE D
M AN U
SC
(b) ceftazidime 2000 mg (administered as ceftazidime-avibactam (PK population).
34
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Supplementary Table Liver function measures for the 41-year old subject in the avibactam group who experience elevated transaminase levels during the repeated-dosing
RI PT
phase of the study.
Day 2
Day 8
Follow up
ALT (U/l)
36
32
522
307
Reference range 17–63
AST (U/l)
21
22
225*
86
15–41
GGT (U/l)
51
55
154
145
7–50
AP (U/l)
82
85
169
Total bilirubin (mg/dl)
0.7
0.9
0.7
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Baseline
38–126
0.6
0.2–1.2
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ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; GGT: gamma glutamyl-transpeptidase.
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*Levels peaked at Day 7 (246 U/l).
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S1341-321X(15)00090-2
DOI:
10.1016/j.jiac.2015.04.006
Reference:
JIC 282
To appear in:
Journal of Infection and Chemotherapy
Received Date: 12 February 2015 Revised Date:
27 March 2015
Accepted Date: 10 April 2015
Please cite this article as: Tominaga N, Edeki T, Li J, Learoyd M, Bouw MR, Das S, Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers, Journal of Infection and Chemotherapy (2015), doi: 10.1016/ j.jiac.2015.04.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Phase I study assessing the safety, tolerability, and
2
pharmacokinetics of avibactam and ceftazidime-avibactam
3
in healthy Japanese volunteers
4
Nobumitsu Tominaga a, Timi Edeki b, James Li c, Maria Learoyd d, M. René Bouw e,
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Shampa Das d *
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a
AstraZeneca, Osaka, Japan
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b
AstraZeneca, Wilmington, DE, USA
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c
AstraZeneca, Waltham, MA, USA
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d
AstraZeneca, Macclesfield, Cheshire, UK
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e
Formerly of AstraZeneca, Mölndal, Sweden
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* Corresponding author: Senior Clinical Pharmacology Scientist, Quantitative Clinical
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Pharmacology, 11G Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG.
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Tel.: +44 1625 230812. E-mail address: [email protected] (Shampa
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Das)
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ACCEPTED MANUSCRIPT ABSTRACT
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Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown to
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restore the in vitro activity of ceftazidime against pathogens producing Ambler class
19
A, C, and some class D β-lactamases. This study aimed to evaluate the safety,
20
tolerability, and pharmacokinetics of single and repeatedmultiple doses of avibactam
21
alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind
22
study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were
23
randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000
24
mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml
25
intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3–6, and once on
26
Day 7. There were no deaths or serious adverse events. Nine treatment-emergent
27
adverse events were reported in three subjects in the avibactam group – including
28
one elevation in transaminase levels, and three vital signs events (tachycardia,
29
palpitations, and orthostatic hypotension) – and one in the ceftazidime-avibactam
30
group. All events were considered mild. After single or repeatedmultiple dosing,
31
plasma concentrations of avibactam and ceftazidime declined in a multi-exponential
32
manner. No plasma concentration accumulation was observed, and the majority of
33
avibactam was excreted unchanged in urine within 24 h. No clinically relevant
34
changes in intestinal bacterial flora were observed. In conclusion, avibactam alone
35
and ceftazidime-avibactam were generally well tolerated in healthy male Japanese
36
subjects, and avibactam pharmacokinetics were comparable whether administered
37
alone or in combination with ceftazidime.
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Keywords: avibactam, ceftazidime, Japanese, safety, tolerability, pharmacokinetics
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1. Introduction There is abundant evidence of increasing antimicrobial resistance in the AsiaPacific region, including resistance among species causing complicated intra-
42
abdominal infections (cIAI), urinary tract infections (cUTI), or nosocomial pneumonia
43
[1–5]. Recent surveillance studies in Japan have also demonstrated an increasing
44
incidence of multi-drug resistant bacterial infections [6–10].
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One of the most common mechanisms for antibiotic drug resistance in Gram-
negative organisms is the production of extended spectrum β-lactamases (ESBLs)
47
[11,12], although bacteria producing AmpC β-lactamases are also spreading
48
[5,13,14]. While carbapenems are still widely used for serious infections caused by
49
potentially β-lactamase-producing pathogens [15], the prevalence of pathogens
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producing carbapenemases, particularly Klebsiella pneumoniae serine
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carbapenemases (KPCs), is a growing threat [11,16].
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activity [17–19]. Avibactam restores the in vitro and in vivo activity of ceftazidime
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against organisms producing Ambler class A ESBLs and carbapenemases (including
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KPC), class C, and some class D enzymes [20–23]. Two multinational Phase II trials
56
of ceftazidime-avibactam in cUTI and cIAI have been completed [24,25], and it is
57
currently undergoing development in a series of multinational Phase III clinical trials
58
in patients with cUTI (NCT01595438, NCT01599806), cIAI (NCT01726023,
59
NCT01499290, NCT01500239), or nosocomial pneumonia (NCT01808092). Two of
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these studies (NCT01595438 and NCT01808092) include patients enrolled at
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multiple centers in Japan.
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The aim of the present study was to investigate the safety, tolerability and
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pharmacokinetics (PK) of avibactam alone and in combination with ceftazidime
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(ceftazidime-avibactam) after single and repeated intravenous (IV) infusion in healthy 3
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Japanese subjects.
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2. Subjects and methods This was a Phase I, randomized, double-blind, placebo-controlled, parallel-group study (NCT01291602) conducted in healthy Japanese volunteers at a single center
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living in the United States.
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The study was approved by the Institutional Review Board, and was performed
in accordance with the ethical principles of the Declaration of Helsinki, consistent with
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Good Clinical Practice and applicable regulatory requirements, and the AstraZeneca
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policy on Bioethics and Human Biological Samples. All subjects provided written,
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informed consent prior to initiation of the study.
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2.1. Subjects
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Healthy male and female Japanese subjects aged 20–45 years, with a body
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mass index (BMI) of 17–27 kg/m2, were eligible for inclusion in the study if they were
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born in Japan, and both their parents and all grandparents were Japanese. They
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were also required to be in possession of a valid Japanese passport, and to have
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been an expatriate of Japan for no more than 5 years. Female subjects were
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required to be of non-childbearing potential, and male subjects had to be willing to
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use double-barrier contraception from the first dose until 3 months after the last dose
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of study drug.
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Subjects were excluded from the study if they had any condition requiring regular
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medication, had used (within the 14 days prior to first dose of study drug) any
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medication known to cause PK drug interaction, or had (within the past 30 days)
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received any other new compound or participated in another clinical study. Other
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exclusion criteria included cardiac abnormalities such as prolonged or shortened QT
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interval (corrected using Fridericia’s formula, QTcF), left or (complete) right bundle
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branch block, Wolff-Parkinson-White syndrome, blood pressure >140/90 mmHg,
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resting heart rate 85 beats per minute (bpm), or family history of unexplained 5
ACCEPTED MANUSCRIPT sudden death or clinically relevant cardiovascular disease. Subjects who smoked
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>5 cigarettes/day, drank >5 cups of coffee/day, or exceeded 21 units of alcohol per
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week were also excluded. Consumption of grapefruit-containing products was not
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permitted from 7 days prior to the first study dose.
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2.2. Treatment
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Eligible subjects were randomized in a 2:2:1 ratio to receive either avibactam
500 mg, or ceftazidime 2000 mg plus avibactam 500 mg, or placebo (0.9% saline),
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each administered as a 100 ml infusion over 2 h.
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Study drug was administered once on Day 1, every 8 h (6 am to 8 am, 2 pm to 4
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pm, and 10 pm to 12 pm) on Days 3–6, and once on Day 7, with a follow-up visit 3–5
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days after the last dosing day. No doses were administered on Day 2. Morning doses
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were administered after an overnight fast of at least 10 h. On Days 3–6, subjects
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fasted for 1 h before and after the second and third doses. Water was permitted
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throughout, as required by subjects.
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No concomitant medication, other than paracetamol (acetaminophen), was allowed without the consent of the investigator. Any paracetamol given had to be
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prescribed by the investigator, and the AstraZeneca Study Team Physician was
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informed.
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Each individual was assigned a unique randomization code using the global
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randomization scheme. The investigator and subjects were blinded to the treatments
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being administered; however, blinding could be broken in the case of a medical
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emergency or unexpected serious adverse event (SAE).
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2.3. Objectives
115 116
The primary objective of the study was to investigate the safety and tolerability of avibactam, alone or in combination with ceftazidime, administered as single and
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ACCEPTED MANUSCRIPT repeatedmultiple IV infusions, in healthy Japanese subjects. Secondary objectives
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were to investigate in healthy Japanese subjects the PK of avibactam, alone and in
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combination with ceftazidime, and the influence of avibactam, alone and in
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combination with ceftazidime, on intestinal bacterial flora.
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2.4. Safety and tolerability
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The safety population was defined as all subjects who received at least one dose of randomized study compound (avibactam, ceftazidime-avibactam, or placebo) and
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for whom any post-dose data were available.
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Safety and tolerability were assessed by evaluation of treatment-emergent adverse events (TEAEs) (defined as those occurring or worsening after the first dose
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of, but not necessarily related to, study compound), SAEs, other significant adverse
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events (OAEs), physical examination, vital signs, electrocardiograms (ECGs), and
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clinical laboratory tests. TEAEs were coded using MedDRA version 12.0 or higher,
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and causal relationship between investigational product and each TEAE was
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assessed by the investigator. Vital signs were measured at regular intervals on Days
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1–7, and 12-lead ECGs were performed pre-dose and then at regular intervals on
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Days 1, 3, and 7, and once (pre-dose) on Days 4, 5, and 6.
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2.5. Pharmacokinetics
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The PK population was defined as all subjects who received at least one dose of
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study compound, completed the study without any major protocol violation, and
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provided evaluable data for the PK analyses.
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Blood samples were collected pre-dose and for 24 h after the start of dosing (at
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0.5, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 4, 6, 8, 12, and 24 h) on Day 1 and Day 7, and pre-
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dose, 2 and 4 h after the start of the morning infusion on Day 3 and Day 5. Urine
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samples were collected on Days 1, 3, and 7 pre-dose then during the periods 0–8 h,
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8–16 h, and 16–24 h. 7
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Ceftazidime and avibactam concentrations in plasma and urine were analyzed by Quotient Bioresearch (Fordham, Cambs., UK) as described previously [26].
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Briefly, prepared plasma and urine samples of each drug were analyzed using ultra-
146
performance liquid chromatography and pneumatic-assisted electrospray
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(TurboIonSpray™, AB SCIEX, Concord, Ontario, Canada) tandem mass
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spectrometry.
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Avibactam concentrations in plasma were assessed over the validated
calibration ranges 10–1,000 ng/ml (low range) and 500–50,000 ng/ml (high range) in
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human plasma, with a validated dilution of 10-fold with human plasma. The lower
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limit of quantification (LLOQ) was previously established as 10 and 500 ng/ml,
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respectively, during the method validation. Comparing quality control (QC) samples,
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the between-assay precision (% coefficient of variation [CV]) ranged from 3.0–5.4%
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and 0.3–6.5% for the avibactam high and low calibration range, respectively.
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validated calibration ranges 87.4–2,620 ng/ml and 100–5,000 ng/ml in human urine,
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respectively, with a validated dilution of 5,000-fold with human urine. The LLOQ for
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ceftazidime was established as 87.4 ng/ml during the method validation. The
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between-assay precision (%CV) for the ceftazidime and avibactam assay ranged
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from 4.9–8.4% and 2.6–5.9%, respectively.
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Data collection and peak integration were performed using Analyst software
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(version 1.4.2 and 1.5.1). Standard regression and quantitation were performed using
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Watson LIMS (version 7.2).
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167 168
Plasma PK parameters for avibactam and ceftazidime were determined on Day 1 (single-dose) and Day 7 (multiple-dose), including: Single-dose parameters: maximum concentration (Cmax), time of maximum concentration (tmax), area under the curve (AUC) from time 0 to infinity (AUC), 8
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elimination half-life (t½), volume of distribution at steady state (Vss), and clearance
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(CL). Multiple-dose parameters: Cmax at steady state (Cmax ss), tmax at steady state, AUC
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during the dosing interval at steady state (AUCτ), t½ at steady state, Vss, CL at steady
173
state, accumulation ratio for Cmax, calculated as Cmax ss Day 7/Cmax Day 1,
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accumulation ratio for AUC, calculated as AUCτ Day 7/AUCτ Day 1, temporal
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change parameter (TCP), calculated as AUCτ Day 7/AUC Day 1.
The amount of drug excreted unchanged in urine (Ae), the fraction of the dose
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excreted in urine (Fe) and renal CL were also determined for avibactam and
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ceftazidime.
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The PK results reported below focus on avibactam as the novel entity in the study, but PK data for ceftazidime are included in the tables and figure.
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2.6. Intestinal bacterial flora
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Fecal samples were collected for analysis of intestinal bacterial flora on Day –1, Days 5 and 8, and at the follow-up visit. Aerobic and anaerobic bacteria were
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identified, quantitated and evaluated for change from baseline analysis.
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2.7. Statistical analysis
No formal statistical hypothesis testing was performed. The aim was to enroll 15
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subjects overall. Missing data were excluded from all analyses (i.e., there was no
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imputation of data), and any extreme values relative to the majority of data were
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included.
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Continuous safety variables were summarized using descriptive statistics, and
191
adverse events (AEs) summarized by treatment group. Clinical laboratory test values
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were presented for each subject, with abnormal values flagged. Plasma and urine PK
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parameters for avibactam and ceftazidime were summarized using descriptive 9
ACCEPTED MANUSCRIPT statistics, including geometric mean, and CV for the geometric mean. Findings for
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intestinal bacterial flora were presented using descriptive statistics.
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3. Results The study was conducted between 17 February and 8 April 2011. Sixteen
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subjects (all male) were enrolled in the study and randomized. All subjects except
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one completed the study. One subject randomized to ceftazidime-avibactam
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withdrew consent after the morning dose on Day 3, but data obtained up to that point
201
were used in the safety and PK analyses. Baseline characteristics of all subjects are
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shown in Table 1. Mean age in subjects in the placebo group was older than in
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subjects in the avibactam and ceftazidime-avibactam groups, and mean weight and
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BMI varied somewhat across the treatment groups. None of these differences were
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expected to impact the overall interpretation of safety and PK data.
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3.1. Safety
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There were no deaths, SAEs, or TEAEs that led to discontinuation from the study during single- or repeatedmultiple-dose administration of avibactam or
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ceftazidime-avibactam. During the single-dose period of avibactam alone, one TEAE
210
(tachycardia) was reported (Table 2). During repeatedmultiple-dose administration,
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seven TEAEs were reported by two subjects in the avibactam group (palpitations,
212
chest discomfort, infusion site reactions, dyspnoea, contact dermatitis, and increased
213
transaminases) and one TEAE (orthostatic hypotension) was reported in a subject in
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the ceftazidime-avibactam group (Table 2). All TEAEs except contact dermatitis were
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considered related to study compound, and all were considered mild in severity.
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There was only one clinically significant change in laboratory values (reported as
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an OAE), a mild increase in transaminase levels during the repeatedmultiple-dosing
218
phase in a 41-year old subject in the avibactam group: alanine aminotransferase
219
(ALT), aspartate aminotransferase (AST), gamma glutamyl-transpeptidase (GGT)
220
and alkaline phosphatase (AP) increased above the reference ranges between Day 2
221
and Day 8, while total bilirubin remained within the reference range throughout the
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223
allergies. He remained asymptomatic, and all other laboratory test results were within
224
clinically acceptable limits. Although his transaminase levels had not normalized by
225
the end of the study, most liver-related test values were decreasing at the follow-up
226
visit 3 days after the last dose of study drug (ALT 307 U/l, AST 86 U/l, GGT 145 U/l,
227
AP 171 U/l, total bilirubin 0.6 mg/dl). The subject was lost to follow-up thereafter.
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Two subjects in the ceftazidime-avibactam group had minor increases in liver
229
enzymes: one had minor elevations in ALT on Day 8 and at follow-up (67 and 77 U/l,
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respectively), and in AST at follow-up (48 U/l); the other had a mild elevation in ALT
231
at follow-up (80 U/l), and raised total bilirubin on Days 2 and 8 (1.4 and 1.5 mg/dl,
232
respectively).
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There were no clinically significant abnormalities in ECG data at any time point, no AEs related to ECG measurements and no clinically significant findings on
235
physical examination.
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3.2. Pharmacokinetic analysis
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Fig. 1 shows the geometric mean plasma avibactam concentration–time curves (log scale) for avibactam and ceftazidime-avibactam following single-dose (Day 1)
239
and repeatedmultiple-dose (Day 7) administration. The plasma Cmax of both
240
avibactam and ceftazidime was achieved at the end of the IV infusion, after which
241
plasma concentrations declined in a multi-exponential manner.
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Plasma PK parameters for avibactam and ceftazidime are summarized in Table
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3 (single-dose, Day 1) and Table 4 (repeatedmultiple-dose, Day 7). The mean half-
244
life of avibactam was 1.4 h following single or multiple doses alone or in combination
245
with ceftazidime. No plasma accumulation was observed for avibactam or
246
ceftazidime after repeatedmultiple-dose administration. The trough concentrations
247
were comparable for study Days 5 and 7 (data not shownFig. 2) and accumulation 12
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249
ratios for AUCτ (RacAUC) were approximately 1 (Table 4). The majority of avibactam was excreted unchanged in the urine within 24 h (Table 5). Following single-dose administration on Day 1, the mean percentage of
251
avibactam excreted in urine was 73.2% for avibactam alone and 86.5% when given
252
in combination with ceftazidime. Following multiple-dose administration, the mean
253
percentage of the avibactam dose excreted in urine on Day 7 was 99.5% for
254
avibactam alone, and 95.8% when given in combination with ceftazidime. Avibactam
255
mean renal CL when given alone and in combination with ceftazidime was
256
approximately 8.8 l/h (±standard definitiondeviation [SD] 4.03 l/h) and 9.5 l/h (±SD
257
1.658 l/h), respectively, similar to the total plasma CL for avibactam (Tables 3 and 4),
258
showing that avibactam is predominantly renally excreted in Japanese subjects.
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The results indicate that the PK of avibactam were not altered when administered in the presence of ceftazidime following either single or multiple daily
261
doses in Japanese subjects, that the PK of ceftazidime were comparable following
262
single and multiple dosing in the presence of avibactam, and that the majority of both
263
avibactam and ceftazidime is excreted unchanged.
264
3.3. Intestinal bacterial flora
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There were no clinically relevant trends observed for changes in intestinal bacterial flora with avibactam alone.
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With ceftazidime-avibactam, slight increases were observed in two aerobic
268
species (Lactobacillus spp. and Enterococcus faecalis) Days 5–Day 10 and two
269
anaerobic species (Peptostreptococcus spp, from Days 5–Day 10 and
270
Bifidobacterium spp.) Days 5–Day 8 (Table 6), but these were not considered
271
clinically relevant, and there was no associated AE of diarrhea.
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4. Discussion The safety and pharmacokinetics of ceftazidime-avibactam have not been
274
investigated previously in Japanese subjects. Safety and tolerability findings in this
275
study were similar to those seen in studies that included healthy White, Black, African
276
and Asian subjects (NCT01395420; NCT01430910; NCT01534247) [27–31], with no
277
new safety concerns being identified. One individual in this study had changes in liver
278
function parameters during treatment with avibactam that were potentially clinically
279
significant, but there were no associated clinical safety concerns, and no reported
280
transaminase elevations in any other subjects treated with avibactam or ceftazidime-
281
avibactam in this study, nor in other studies carried out to date [24,25,27–31].
282
As in the present study, previous investigations in non-Japanese subjects
283
showed no evidence of drug–drug interaction between ceftazidime and avibactam,
284
with comparable PK of both agents after single and multiple dosing, and no obvious
285
accumulation of either component [27]. Similarly, CL of avibactam and ceftazidime
286
has been shown to be predominantly renal in both the small cohort of Japanese
287
subjects in the present study and in non-Japanese subjects investigated previously,
288
with the majority of both drugs excreted unchanged in urine [28,29]. In those studies,
289
avibactam AUC and t½ were similar. In single- and multiple-ascending dose studies in
290
healthy male (non-Japanese) volunteers, avibactam pharmacokinetics were shown to
291
be linear, with dose-proportional increase in exposure [29]. Ceftazidime exposure
292
was lower in non-Japanese subjects [28–30] compared with Japanese subjects in the
293
present study. The small increase in ceftazidime exposure observed in the present
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study was not considered to have an impact on the dose recommendation for
295
ceftazidime-avibactam in Japanese patients.
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Analysis of microbiological data from the current study, in addition to the absence of any AE of diarrhea, suggests there may be no clinically significant
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changes in intestinal bacterial flora with ceftazidime and avibactam. The dosage regimen chosen for this study (ceftazidime 2000 mg plus avibactam 500 mg) reflects that currently under investigation in ongoing Phase III studies, and
301
was based on the results of in vitro susceptibility testing, hollow fiber experiments
302
and preclinical data [20,32–34], first-in-man studies in healthy Western subjects,
303
which demonstrated an acceptable safety and tolerability profile [29] and a Phase II
304
study in cIAI [24].
Despite inclusion criteria allowing the enrollment of females, none participated in
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this study. However, a previous study in healthy American subjects in the U.S.A.
307
indicated that there were no significant gender differences in terms of avibactam PK
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[31].
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While the clinical trial program is ongoing, on 25 February 2015, the U.S. Food and Drug Administration gave approval, based on data from the Phase II program,
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for the use of ceftazidime-avibactam in the treatment of adults with cIAI, in
312
combination with metronidazole, or cUTI including kidney infections (pyelonephritis),
313
who have limited or no alternative treatment options [35]. In conclusion, avibactam alone and ceftazidime-avibactam were generally well
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tolerated at the doses tested when administered as single and multiple doses in
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healthy male Japanese subjects. There were no deaths, SAEs, or clinically significant
317
ECG changes. The PK of avibactam and ceftazidime following either single or
318
multiple daily doses were comparable whether administered alone or in combination,
319
and there was no plasma accumulation of either drug. Overall, these findings indicate
320
that ceftazidime-avibactam exposure and tolerability are comparable in Japanese
321
and non-Japanese subjects, and support the future evaluation of ceftazidime-
322
avibactam in clinical trials in Japanese patients.
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Conflict of interest N. Tominaga, T. Edeki, J. Li, S. Das and M. Learoyd are employees of AstraZeneca. M.R. Bouw was an employee of AstraZeneca at the time the study was
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carried out and during the development of the manuscript.
328
Acknowledgments
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The authors would like to thank Mark Yen, MD, California Clinical Trials, Glendale, CA, USA, the Principal Investigator for the study. This study was
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sponsored by AstraZeneca.
Medical writing support was provided by Liz Anfield and Catherine Savage of
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Prime Medica Ltd, Knutsford, Cheshire and funded by AstraZeneca. The design and
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conduct of the study, as well as analysis of the study data and opinions, conclusions,
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and interpretation of the data, are the responsibility of the authors.
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References [1] Hsueh PR, Hoban DJ, Carmeli Y, Chen SY, Desikan S, Alejandria M, et al. Consensus review of the epidemiology and appropriate antimicrobial therapy
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of complicated urinary tract infections in Asia-Pacific region. J Infect
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2011;63:114-23.
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[2] Liu YM, Chen YS, Toh HS, Huang CC, Lee YL, Ho CM, et al. In vitro
susceptibilities of non-Enterobacteriaceae isolates from patients with intra-
343
abdominal infections in the Asia-Pacific region from 2003 to 2010: results
344
from the Study for Monitoring Antimicrobial Resistance Trends (SMART). Int J
345
Antimicrob Agents 2012;40 Suppl:S11-S17.
M AN U
346
SC
342
[3] Lu PL, Liu YC, Toh HS, Lee YL, Liu YM, Ho CM, et al. Epidemiology and antimicrobial susceptibility profiles of Gram-negative bacteria causing urinary
348
tract infections in the Asia-Pacific region: 2009-2010 results from the Study
349
for Monitoring Antimicrobial Resistance Trends (SMART). Int J Antimicrob
350
Agents 2012;40 Suppl:S37-S43.
[4] Rosenthal VD, Bijie H, Maki DG, Mehta Y, Apisarnthanarak A, Medeiros EA,
EP
351
TE D
347
et al. International Nosocomial Infection Control Consortium (INICC) report,
353
data summary of 36 countries, for 2004-2009. Am J Infect Control
354
355 356
AC C
352
2012;40:396-407.
[5] Sheng WH, Badal RE, Hsueh PR. Distribution of extended-spectrum blactamases, AmpC b-lactamases, and carbapenemases among
357
Enterobacteriaceae isolates causing intra-abdominal infections in the Asia-
358
Pacific region: results of the study for Monitoring Antimicrobial Resistance
359
Trends (SMART). Antimicrob Agents Chemother 2013;57:2981-8.
17
ACCEPTED MANUSCRIPT 360
[6] Fujiwara M, Mizunaga S, Nomura N, Mitsuyama J, Hashido H, Yamaoka K, et
361
al. [Sensitivity surveillance of Pseudomonas aeruginosa isolates for several
362
antibacterial agents in Gifu and Aichi prefecture (2008)]. Jpn J Antibiot
363
2012;65:15-26. [7] Kuroda H, Yano H, Hirakata Y, Arai K, Endo S, Kanamori H, et al. Molecular
RI PT
364
characteristics of extended-spectrum b-lactamase-producing Escherichia coli
366
in Japan: emergence of CTX-M-15-producing E. coli ST131. Diagn Microbiol
367
Infect Dis 2012;74:201-3.
368
SC
365
[8] Izumida M, Nagai M, Ohta A, Hashimoto S, Kawado M, Murakami Y, et al. Epidemics of drug-resistant bacterial infections observed in infectious disease
370
surveillance in Japan, 2001-2005. J Epidemiol 2007;17 Suppl:S42-S47.
371
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[9] Nakano R, Nakano A, Abe M, Inoue M, Okamoto R. Regional outbreak of CTX-M-2 b-lactamase-producing Proteus mirabilis in Japan. J Med Microbiol
373
2012;61:1727-35.
374
TE D
372
[10] Watanabe A, Yanagihara K, Matsumoto T, Kohno S, Aoki N, Oguri T, et al. Nationwide surveillance of bacterial respiratory pathogens conducted by the
376
Surveillance Committee of Japanese Society of Chemotherapy, Japanese
377
Association for Infectious Diseases, and Japanese Society for Clinical
379
380 381
382
AC C
378
EP
375
Microbiology in 2009: general view of the pathogens' antibacterial susceptibility. J Infect Chemother 2012;18:609-20.
[11] Bush K. Proliferation and significance of clinically relevant b-lactamases. Ann N Y Acad Sci 2013;1277:84-90. [12] Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against
383
resistant gram-negative organisms: extended-spectrum b-lactamase-
384
producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, 18
ACCEPTED MANUSCRIPT 385
and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc
386
2011;86:250-9.
387
[13] Gutkind GO, Di CJ, Power P, Radice M. b-lactamase-mediated resistance: a biochemical, epidemiological and genetic overview. Curr Pharm Des
389
2013;19:164-208.
390
RI PT
388
[14] Matsumura Y, Yamamoto M, Higuchi T, Komori T, Tsuboi F, Hayashi A, et al. Prevalence of plasmid-mediated AmpC b-lactamase-producing Escherichia
392
coli and spread of the ST131 clone among extended-spectrum b-lactamase-
393
producing E. coli in Japan. Int J Antimicrob Agents 2012;40:158-62.
M AN U
394
SC
391
[15] Vardakas KZ, Tansarli GS, Rafailidis PI, Falagas ME. Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to
396
Enterobacteriaceae producing extended-spectrum b-lactamases: a
397
systematic review and meta-analysis. J Antimicrob Chemother 2012;67:2793-
398
803.
401 402 403
404
Enterobacteriaceae. Emerg Infect Dis 2011;17:1791-8.
EP
400
[16] Nordmann P, Naas T, Poirel L. Global spread of Carbapenemase-producing
[17] Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, et al. Avibactam is a covalent, reversible, non-b-lactam b-lactamase inhibitor. Proc Natl Acad Sci U
AC C
399
TE D
395
S A 2012;109:11663-8.
[18] Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De LF, Sanyal G, et al.
405
Structural insight into potent broad-spectrum inhibition with reversible
406
recyclization mechanism: avibactam in complex with CTX-M-15 and
407
Pseudomonas aeruginosa AmpC b-lactamases. Antimicrob Agents
408
Chemother 2013;57:2496-505.
19
ACCEPTED MANUSCRIPT 409
[19] Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagace-Wiens
410
PR, et al. Ceftazidime-avibactam: a novel cephalosporin/b-lactamase inhibitor
411
combination. Drugs 2013;73:159-77.
412
[20] Endimiani A, Hujer KM, Hujer AM, Pulse ME, Weiss WJ, Bonomo RA. Evaluation of ceftazidime and NXL104 in two murine models of infection due
414
to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother
415
2011;55:82-5.
[21] Lagace-Wiens PR, Tailor F, Simner P, DeCorby M, Karlowsky JA, Walkty A,
SC
416
RI PT
413
et al. Activity of NXL104 in combination with b-lactams against genetically
418
characterized Escherichia coli and Klebsiella pneumoniae isolates producing
419
class A extended-spectrum b-lactamases and class C b-lactamases.
420
Antimicrob Agents Chemother 2011;55:2434-7.
421
M AN U
417
[22] Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against
423
carbapenemase-producing Enterobacteriaceae. Antimicrob Agents
424
Chemother 2011;55:390-4.
EP
TE D
422
[23] Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C,
426
et al. In vitro activity of the b-lactamase inhibitor NXL104 against KPC-2
427 428
AC C
425
carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 2009;64:326-9.
429
[24] Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of
430
the efficacy and safety of ceftazidime/avibactam plus metronidazole versus
431
meropenem in the treatment of complicated intra-abdominal infections in
432
hospitalized adults: results of a randomized, double-blind, Phase II trial. J
433
Antimicrob Chemother 2013;68:1183-92.
20
ACCEPTED MANUSCRIPT [25] Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka
435
J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-
436
cilastatin in the treatment of complicated urinary tract infections, including
437
acute pyelonephritis, in hospitalized adults: results of a prospective,
438
investigator-blinded, randomized study. Curr Med Res Opin 2012;28:1921-31.
439
RI PT
434
[26] Das S, Armstrong J, Mathews D, Li J, Edeki T. Randomized, placebo-
controlled study to assess the impact on QT/QTc interval of supratherapeutic
441
doses of ceftazidime-avibactam or ceftaroline fosamil-avibactam. J Clin
442
Pharmacol 2014;54:331-40.
[27] Edeki T, Armstrong J, Li J.Pharmacokinetics of avibactam (AVI) and
M AN U
443
SC
440
ceftazidime (CAZ) following separate or combined administration in healthy
445
volunteers. 53rd International Conference on Antimicrobial Agents and
446
Chemotherapy (ICAAC), September 10-13, 2013, Denver, CO, USA (Abstract
447
A-1019).
448
TE D
444
[28] Li J, Armstrong J, Edeki T.Pharmacokinetic (PK) drug interaction study of ceftazidime-avibactam (CAZ-AVI) and metronidazole (MTZ) in healthy
450
volunteers. Poster presented at the 53rd International Conference on
451
Antimicrobial Agents and Chemotherapy (ICAAC), September 10-13, 2013,
452
Denver, CO, USA.
454
AC C
453
EP
449
[29] Merdjan H, Rangaraju M, Tarral A. Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with
455
ceftazidime in healthy male volunteers: results of two randomized, placebo-
456
controlled studies. Clin Drug Invest 2015;In press.
457 458
[30] Nicolau DP, Siew L, Armstrong J, Edeki T, Bouw R.Concentration of avibactam (AVI) and ceftazidime (CAZ) in plasma and epithelial lining fluid
21
ACCEPTED MANUSCRIPT 459
(ELF) in healthy volunteers. International Conference on Antimicrobial Agents
460
and Chemotherapy (ICAAC), September 10-13, 2013, Denver, CO, USA
461
(Abstract A-1027).
462
[31] Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of avibactam in healthy volunteers. Clin Ther 2015;Mar 10 (epub ahead
464
of print).
465
RI PT
463
[32] Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in
combination with b-lactams against Klebsiella pneumoniae isolates producing
467
KPC carbapenemases. Antimicrob Agents Chemother 2009;53:3599-601.
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SC
466
[33] Levasseur P, Girard AM, Miossec C, Pace J, Coleman K. In vitro antibacterial
469
activity of the ceftazidime-avibactam combination against Enterobacteriaceae,
470
including strains with well-characterized beta-lactamases. Antimicrob Agents
471
Chemother 2015;59:1931-4.
TE D
468
[34] Coleman K, Levasseur P, Girard AM, Borgonovi M, Miossec C, Merdjan H, et
473
al. Activities of ceftazidime and avibactam against beta-lactamase-producing
474
Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob
475
Agents Chemother 2014;58:3366-72.
477 478 479
[35]
AVYCAZ Prescribing Information. 2015;Available at:
AC C
476
EP
472
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206494lbl.pdf. Accessed 16 March 2015.
480
22
ACCEPTED MANUSCRIPT 481
Table 1
482
Subject demographics (safety population).
Ceftazidimeavibactam
Placebo
(n = 6)
(n = 7)
(n = 3)
(n = 16)
Age, years
28.8 (6.7)
25.4 (3.3)
36.7 (9.3)
28.8 (7.0)
Male, n (%)
6 (100)
7 (100)
3 (100)
16 (100)
Height, cm
175.2 (4.8)
170.7 (3.5)
174.3 (6.7)
173.1 (4.8)
Weight, kg
73.3 (9.9)
63.3 (4.6)
78.3 (7.4)
69.9 (9.4)
2
24.0 (2.2)
21.9 (1.6)
25.7 (0.6)
23.4 (2.2)
SC
M AN U
BMI, kg/m
BMI: body mass index.
484
Data are mean (standard deviation), unless otherwise stated.
AC C
EP
TE D
483
All subjects
RI PT
Avibactam
23
ACCEPTED MANUSCRIPT 485
Table 2
486
TEAEsa regardless of perceived relationship to study drug (safety population).
Ceftazidimeavibactam
(n = 6)
(n = 7)
(n = 3)
1
0
0
b
1
0
0
2
1
0
c
0
0
c
0
0
d
0
0
d
0
0
d
0
0
c
0
0
M AN U
Tachycardia
SC
Single-dose period
Any AE n
RepeatedMultiple-dose period
Any AE, n
1
Chest discomfort
TE D
Palpitations
1
1
Infusion site thrombosis
1
EP
Infusion site extravasation
AC C
Transaminases increased
Placebo
RI PT
Avibactam alone
1
Dyspnoea
1
Contact dermatitis
1
c
0
0
Orthostatic hypotension
0
1
0
487
a
488
study medication; AE counts are at the subject level; preferred term counts are at the event level;
489
c
490
AE: adverse event; TEAE: treatment-emergent adverse events.
All AEs were considered to be mild and all except contact dermatitis were considered to be related to b
d
Occurred in the same individual; Occurred in the same individual.
24
ACCEPTED MANUSCRIPT Table 3
492
Single-dose avibactam and ceftazidime plasma PK parameters on Day 1a following
493
treatment with avibactam 500 mg alone or avibactam 500 mg plus ceftazidime 2000
494
mg (PK population)
Avibactam
(avibactam alone
(ceftazidime-
group)
avibactam group)
PK parameter
n=6
n=7
b
2.0 (2.0, 2.0)
2.0 (2.0, 2.0)
2.0 (2.0, 2.1)
Cmax (µg/ml)
15.1 (9.2)
15.9 (13.6)
110.0 (13.9)
AUC
43.1 (12.3)
45.5 (12.2)
354.0 (13.0)
1.4 (0.1)
1.7 (0.2)
18.3 (15.3)
12.4 (14.0)
11.0 (12.2)
5.6 (13.0)
c
Vss (l)
CL (l/h)
1.4 (0.1)
19.7 (16.2)
TE D
t½ (h)
11.6 (12.3)
Ceftazidime
(ceftazidime-avibactam group) n=7
SC
tmax (h)
RI PT
Avibactam
M AN U
491
a
Values are geometric mean (coefficient of variation [%]) unless stated otherwise; Median (range);
496
c
Mean (standard deviation).
497
AUC: area under the curve; CL: clearance; Cmax, maximum concentration; PK: pharmacokinetic; t½,
498
terminal elimination half-life; tmax, time of maximum concentration; Vss: volume of distribution at steady
499
state.
AC C
500
b
EP
495
25
ACCEPTED MANUSCRIPT Table 4
502
Multiple-dose avibactam and ceftazidime plasma PK parameters on Day 7a after
503
treatment with avibactam 500 mg alone or avibactam 500 mg plus ceftazidime 2000
504
mg, administered once on Day 1, every 8 h on Days 3 to 6, and once on Day 7 (PK
505
population)
Avibactam
(avibactam alone
(ceftazidime-
group)
avibactam group) b
Ceftazidime
(ceftazidime-avibactam group)
SC
Avibactam
RI PT
501
n=6
n=6
Cmax,ss (µg/ml)
14.8 (11.8)
15.0 (20.6)
113.0 (15.3)
AUCτ (µg·h/ml)
41.5 (9.6)
42.2 (14.4)
348.2 (17.2)
c
1.4 (0.2)
1.4 (0.1)
1.7 (0.1)
11.9 (14.4)
5.7 (17.2)
1.0 (8.3)
0.9 (12.4)
1.0 (12.5)
1.0 (6.8)
0.9 (7.8)
1.0 (8.5)
0.9 (8.1)
1.0 (9.6)
t½,ss (h)
RacAUC
TCP
EP
RacCmax
12.1 (9.6)
TE D
CLss (l/h)
M AN U
PK parameter
1.0 (6.5)
b
n=6
506
a
b
507
were unavailable for one subject in the ceftazidime-avibactam group who withdrew consent and
508
discontinued after Day 3 dosing; Mean (standard deviation).
509
AUCτ: AUC during the dosing interval from 0–8 h; CLss: clearance at steady state; Cmax,ss: maximum
510
concentration at steady state; PK: pharmacokinetic; RacAUC: accumulation ratio for AUCτ, calculated as
511
AUCτ Day 7/AUCτ Day 1; RacCmax: accumulation ratio for Cmax, calculated as Cmax ss Day 7/Cmax Day 1;
512
t½ ss: terminal elimination half-life at steady state; tmax,ss: time of maximum concentration at steady state;
513
TCP: temporal change parameter, calculated as AUCτ Day 7/AUC Day 1.
AC C
Values are geometric mean (geometric coefficient of variation [%]) unless stated otherwise; Data
c
514
26
ACCEPTED MANUSCRIPT Table 5
516
Single- and multiple-dose avibactam and ceftazidime urine pharmacokinetic
517
parameters for cumulative 24-h intervala after treatment with avibactam 500 mg alone
518
or avibactam 500 mg plus ceftazidime 2000 mg, administered once on Day 1, every
519
8 h on Days 3 to 6, and once on Day 7 (PK population).
PK parameter
RI PT
515
Ae (mg)
Fe (%)
Day 1
366 (147.0)
73.2 (29.5)
8.82 (4.03)
Day 3
1,220 (287.0)
81.4 (19.1)
NQ
Day 7
498 (27.1)
99.5 (5.4)
NQ
432 (65.4)
86.5 (13.1)
9.53 (1.58)
1,180 (132.0)
78.9 (8.8)
NQ
479 (64.5)
95.8 (12.9)
NQ
Day 1
1,800 (245.0)
90.1 (12.2)
5.82 (0.82)
Day 3
4,530 (392.0)
76.5 (6.5)
NQ
Day 7
1,930 (84.1)
96.5 (4.2)
NQ
M AN U
alone group), n = 6
b
Day 3
AC C
Day 7
EP
Day 1
TE D
Avibactam (ceftazidimeavibactam group), n = 7
SC
Avibactam (avibactam
CLR (L/h)
Ceftazidime (ceftazidimeb
avibactam group), n = 7
27
ACCEPTED MANUSCRIPT a
Values are arithmetic mean (standard deviation).
521
b
n = 6 for Day 3 and Day 7 because data were unavailable for one subject in the ceftazidime-avibactam
522
group (discontinued after Day 3 dosing).
523
Ae: cumulative amount excreted; CLR: renal clearance; Fe: percentage of
524
cumulated urinary recovery; NQ: non-quantifiable; PK: pharmacokinetic.
AC C
EP
TE D
M AN U
SC
RI PT
520
28
ACCEPTED MANUSCRIPT
RI PT
Table 6 Mean (SD) change from baseline in intestinal flora during treatment with avibactam 500 mg alone, avibactam 500 mg plus ceftazidime 2000
SC
mg, or placebo, administered once on Day 1, every 8 h on Days 3–6, and once on Day 7: log (observed/baseline ratio) (safety population)
Organism
Ceftazidime-avibactam (n = 7)
Day 8
Day 10
Day 5
Day 8
Day 10
Day 5
Day 8
Day 10
3
5
2
3
4
3
2
1
1
–3.96
–8.13
a
TE D
–0.35 (1.63)
–2.42 (1.96) –5.76 (0.59)
Candida spp.
Mean (SD)
1
–1.35
2
1
AC C
n
EP
Mean (SD)
Placebo (n = 3)
Day 5
Baccilus spp.
n
M AN U
Avibactam alone (n = 6)
–1.78 (0.04)
–0.32
–2.77 (5.60) –3.39 (4.18)
0
–2.91 (2.52) –5.22 (6.47)
0
1
–2.11
Enterococcus avium
29
ACCEPTED MANUSCRIPT
Mean (SD)
1
1
1
2.04
1.16
0.06
1
1
1
1
–1.61
0.61
1.70
–0.13
1
1
RI PT
n
Mean (SD)
n
0
5.65
Escherichia coli
Mean (SD)
2
–0.56 (1.36)
3
4
AC C
n
4.85 (3.15)
1
1.75
1.90
1
0
0
6.21
0
0
13.12
EP
Mean (SD)
TE D
Enterococcus faecium
2
M AN U
n
SC
Enterococcus faecalis
1
–4.99 (4.28) –3.03 (5.42)
1
3
3
3
–5.86
0.86 (3.82)
0.90 (1.88)
1.39 (2.30)
30
ACCEPTED MANUSCRIPT
RI PT
Klebsiella pneumoniae
n
3
2
0.26 (2.06)
0.54 (1.70)
1.72 (1.18)
2
2
2
Mean (SD)
–1.61 (4.43)
Streptococcus, viridans group
n
5
–3.18 (2.15) –1.92 (2.71)
AC C
n
1.71
EP
Staphylococcus aureus
1
TE D
Mean (SD)
4
M AN U
Lactobacillus spp.
n
1
1
6.69
2.05
7.59
1
1
1
6.28
–0.46
1.15
0
1
1
–1.14
2.4
1
1
SC
Mean (SD)
1
4
5
0
0
31
ACCEPTED MANUSCRIPT
–1.70 (1.49)
–0.54 (1.38) –0.10 (2.57)
Bacteroides fragilis
6
6
3
0.50 (7.59)
0.57 (2.03)
1.36 (5.33)
3
2
3
–5.26 (2.68)
–1.33 (0.43)
0.02 (3.46)
6
6
–1.07 (7.06)
0.34 (3.85)
Mean (SD)
Clostridium spp.
5
AC C
Mean (SD)
EP
Bifidobacterium spp.
n
5
3
3
3
1.22 (9.68)
1.82 (5.46)
1.50 (3.59)
0.82 (3.38)
–0.08 (2.83)
–0.36 (0.85)
1
1
1
1
3.49
2.51
4.45
0.92
1
1
3
3
3
–1.43
5.05
–2.97 (12.04)
0.58 (1.45)
2.29 (1.84)
TE D
Bacteroides spp.
n
0.22
3
M AN U
Mean (SD)
6
0.51 (1.53)
SC
group
n
1.74
RI PT
Mean (SD)
32
ACCEPTED MANUSCRIPT
Mean (SD)
5
4
4
1
–0.26 (1.98)
–0.25 (3.17)
1.19 (7.01)
–2.94
2
2
2
0.37 (8.33)
0.42 (0.01)
2.31 (4.12)
Mean (SD)
Peptostreptococcus
n
0
0
3
3
3
2.94 (1.19)
4.11 (3.17)
4.06 (8.06)
1
–1.04
1
1
–1.95
6.06
0
EP
Mean (SD)
TE D
spp.
0
M AN U
n
0
SC
Fusobacterium spp.
0
RI PT
n
AC C
Values are mean (SD) natural logarithm (observed/baseline) CFU/g, except where only one patient, individual value is shown and SD is not applicable. Where n = 0, the ratio of that organism in that treatment group is equal to 1. Where n value is missing, there is no ratio for that organism in that treatment group. a
Not anthracis.
CFU: colony forming unit; SD: standard deviation.
33
ACCEPTED MANUSCRIPT Fig. 1. Geometric mean (± SD) plasma concentration–time curves following singledose administration (Day 1) and multiple-dose administration every 8 h (Day 7) administration of (a) avibactam 500 mg (alone or as ceftazidime-avibactam) and (b) ceftazidime 2000 mg (administered as ceftazidime-avibactam) (semi-log scale) (PK
RI PT
population). Fig. 2. Geometric mean (± SD) trough plasma concentration–time data on Days 5 and 7 for (a) avibactam 500 mg (alone or as ceftazidime-avibactam) and
AC C
EP
TE D
M AN U
SC
(b) ceftazidime 2000 mg (administered as ceftazidime-avibactam (PK population).
34
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Supplementary Table Liver function measures for the 41-year old subject in the avibactam group who experience elevated transaminase levels during the repeated-dosing
RI PT
phase of the study.
Day 2
Day 8
Follow up
ALT (U/l)
36
32
522
307
Reference range 17–63
AST (U/l)
21
22
225*
86
15–41
GGT (U/l)
51
55
154
145
7–50
AP (U/l)
82
85
169
Total bilirubin (mg/dl)
0.7
0.9
0.7
SC
Baseline
38–126
0.6
0.2–1.2
M AN U
171
ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; GGT: gamma glutamyl-transpeptidase.
AC C
EP
TE D
*Levels peaked at Day 7 (246 U/l).
1
