AAC Accepted Manuscript Posted Online 8 September 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.01713-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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REVISED MANUSCRIPT – Control Number AAC0713-15

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Plasma, Epithelial Lining Fluid, and Alveolar Macrophage

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Concentrations of Meropenem-RPX7009 in Healthy Adult Subjects

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Wenzler E1, Gotfried MH2, Loutit JS3, Durso S3, Griffith DC3, Dudley MN3, Rodvold KA1,4#

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College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA, 2Pulmonary

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Associates, Phoenix, AZ, USA, 3The Medicines Company, San Diego, CA, USA, 4College of

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Medicine, University of Illinois at Chicago, Chicago, IL, USA

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Running title: Intrapulmonary pharmacokinetics of meropenem-RPX7009

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Key Words: meropenem, RPX7009, epithelial lining fluid, alveolar macrophages,

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intrapulmonary, penetration, lung

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All correspondence to:

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Keith A. Rodvold, PharmD, FCCP, FIDSA

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University of Illinois at Chicago, College of Pharmacy

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833 South Wood Street, Rm 164, M/C 886

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Chicago, IL 60612 USA

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Phone: 312-996-3341

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Fax: 312-413-1797

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Email: [email protected]

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ABSTRACT

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The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in

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plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were

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obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of

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meropenem 2 g / RPX7009 2 g administered every 8 hours, as a 3-hour intravenous (IV)

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infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed

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once in each subject at 1.5, 3.25, 4, 6 or 8 hours after the start of the last infusion. Meropenem

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and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and

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ELF. Mean (± standard deviation) pharmacokinetic parameters of meropenem and RPX7009

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determined from serial plasma concentrations were: Cmax 58.2 ± 10.8 and 59.0 ± 8.4 µg/mL, Vss

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16.3 ± 2.6 and 17.6 ± 2.6 L, CL 11.1 ± 2.1 and 10.1 ± 1.9 L/h, and T1/2 1.03 ± 0.15 and 1.27 ±

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0.21 hours, respectively. The intrapulmonary penetration of meropenem and RPX7009 were

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approximately 63% and 53%, respectively, based on the area under the concentration-time

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curve from 0 to 8 hours (AUC0-8) values of ELF and total plasma concentrations. When

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unbound plasma concentrations were considered, ELF penetration was 65% and 79% for

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meropenem and RPX7009, respectively. Meropenem concentrations in AM were below the

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quantitative limit of detection whereas median concentrations of RPX7009 in AM ranged 2.35 to

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6.94 µg/mL. The results from this study lend support to exploring a fixed combination of

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meropenem 2 g / RPX7009 2 g for the treatment of lower respiratory tract infections caused by

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meropenem-resistant Gram negative pathogens susceptible to the combination of meropenem-

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RPX7009.

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INTRODUCTION The prevalence of multidrug-resistant Enterobacteriaceae is increasing worldwide,

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including those that produce carbapenemases (CRE) (1-4). Carbapenem-resistant Klebsiella

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spp. and E. coli are estimated to cause 9,300 healthcare-associated infections each year in the

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United States (5). The Centers for Disease Control and Prevention recently designated CRE an

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urgent public health threat requiring aggressive monitoring and prevention strategies for

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effective patient management (5). As CRE has become resistant to nearly all available

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antibiotics (6-8), several β-lactamase inhibitors are currently in clinical development including

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potent inhibitors of the Klebsiella pneumoniae carbapenemase (KPC) enzyme. RPX7009 is a novel cyclic boronic acid-based β-lactamase inhibitor that restores the

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activity

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carbapenemases, particularly the KPC enzyme (8). The combination of meropenem and

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RPX7009 has demonstrated potent in vitro activity against serine carbapenemases (9,10). A

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fixed-dose, combination product of meropenem 2 g and RPX7009 2 g (meropenem-RPX7009)

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is currently in Phase 3 clinical investigation for the treatment of complicated urinary tract

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infections, acute pyelonephritis and serious infections due to CRE, including hospital-acquired

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and ventilator-associated pneumonia (NCT02166476 and NCT02168946). The dose of

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RPX7009 is supported by non-clinical toxicology and pharmacokinetic-pharmacodynamic

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studies, in addition to the safety and pharmacokinetics observed in Phase 1 studies in normal

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healthy subjects where single and multiple doses of RPX7009 were assessed alone and in

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combination with meropenem (11, 12).

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of

β-lactams

against

strains

of

Enterobacteriaceae

that

produce

serine

The pulmonary penetration of antimicrobials is considered an important factor in their

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ability to be effective agents in the treatment of lower respiratory tract infections (13, 14).

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Measurement of drug concentrations in epithelial lining fluid (ELF) and alveolar macrophages

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(AM) has become the most practical, reliable and reproducible litmus test to gain confidence in

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the adequate distribution of an antibiotic to the site of infection for the treatment of pneumonia

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(14-17). The primary objective of this study was to determine and compare the plasma, ELF and

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AM concentrations of meropenem and RPX7009 following the IV administration of multiple

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doses of meropenem-RPX7009 to healthy male and female adult subjects. The secondary

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objective of this study was to assess the safety and tolerability of meropenem-RPX7009 in

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healthy adult subjects.

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MATERIALS AND METHODS

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Study design and subjects. This was a phase I, randomized, open-label, multiple-dose

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study that evaluated the safety, tolerability, and pharmacokinetics of an intravenous, fixed-dose

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combination of meropenem-RPX7009 (Carbavance™, The Medicines Company, Parsippany,

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NJ) in healthy adults. This study was approved by the Quorum Review Institutional Review

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Board and conducted in accordance with Good Clinical Practices at Pulmonary Associates

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(Phoenix, AZ). Written informed consent was obtained from each subject before study entry.

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Inclusion criteria included healthy male or female subjects between 18 and 55 years of age,

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body weight between 55 and 100 kg, and body mass index ≥18.5 and ≤29.9 kg/m2. All subjects

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demonstrated no clinically significant abnormalities on medical history, vital signs, physical

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examination, laboratory tests (chemistry, hematology, coagulation, urinalysis) and 12-lead

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electrocardiographs prior to study initiation. Subjects must not have used tobacco- or nicotine-

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containing products within the 6 months preceding study day one.

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Exclusion criteria included pregnant or lactating females (male subjects with female partners

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of childbearing potential were required to remain abstinent or use protocol-defined birth control

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methods), acute or chronic liver disease, known biliary tract abnormalities, test results positive

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for HIV antibody, hepatitis B surface antigen, hepatitis C antibody, drugs or alcohol. Subjects

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with excessive alcohol intake or a history of drug abuse or alcoholism within 2 years prior to

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enrollment were excluded. Subjects who could not undergo a bronchoalveolar lavage (BAL) due

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to significant pulmonary or other disease were also excluded. Subjects could not have had a

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hypersensitivity history or serious adverse reaction to β-lactam agents, lidocaine or

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benzodiazepines. Prescription and nonprescription drugs (including vitamins, herbal or dietary

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supplements) were not allowed within 7 days prior to day 1. Subjects could not have donated

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blood in excess of 500 mL within a 56-day period or plasma within a 7-day period before study

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participation. Subjects with a calculated creatinine clearance