Clinical Therapeutics/Volume ], Number ], 2015
Effect of Age and Sex on the Pharmacokinetics and Safety of Avibactam in Healthy Volunteers Antoine Tarral, MD*; and Henri Merdjan, PharmD† Formerly of Novexel SA, Romainville, France ABSTRACT Purpose: Avibactam is a novel non–β-lactam β-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18–45 years) and elderly (aged Z65 years) volunteers of both sexes. Methods: This was a Phase I, open-label study in which healthy volunteers aged Z18 years were enrolled into 4 cohorts: young male, young female, elderly male, and elderly female (n ¼ 8 in each group). Subjects were excluded if they had any condition requiring regular medication or any other relevant conditions. All subjects received a single dose of avibactam 500 mg/100 mL given intravenously over 30 minutes. Pharmacokinetic measurements included Cmax, Tmax, AUC0–1, plasma clearance, and t½. Findings: Within the two age categories the mean age across male and female subjects was well matched. The majority of subjects in the young cohort were black (≥62.5%), whilst the majority of those in the elderly cohorts were white (≥75%). Mean avibactam plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and slightly lower in elderly women (7.98 L/h). Mean Cmax was similar in young male, young female, and elderly female subjects (33.8, 36.9, and 38.4 mg/mL) but lower in elderly male subjects (26.5 mg/mL). Point estimates comparing the ratio of Cmax in male and female subjects over all age groups suggested that Cmax values were 18% lower (90% CI, 30%–5% lower) in male subjects compared with female subjects. Mean AUC0–1 data were similar between the young male, *
Current affiliation: DNDi Drugs for Neglected Diseases Initiative, Geneva, Switzerland. † Current affiliation: Pharsight Consulting Services Europe, Paris, France.
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young female, and elderly male cohorts (49.86, 49.75, and 52.40 mg h/mL) but higher in elderly women (66.23 mg h/mL). Point estimates comparing the ratio of AUC0–1 in elderly and young subjects across both sexes suggested that AUC0–1 values were 17% higher (90% CI, 5%–31%) in elderly subjects compared with young subjects. The t½ was slightly longer for elderly subjects compared with younger subjects. The most common adverse event was administration/venipuncture site bruising (6 events); all adverse events were mild. Implications: No notable differences in pharmacokinetics were observed between the male and female cohorts. The generalizability of the study is limited due to its small sample size. However, the small differences observed between the young and elderly cohorts are not sufficient to warrant dosing adjustments based on age. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: age, avibactam, pharmacokinetics, sex.
INTRODUCTION Gram-negative pathogens are responsible for a large proportion of nosocomial infections,1 as well as those acquired in the community. Gram-negative organisms have developed highly efficient mechanisms for antibiotic drug resistance,2 with the production of extendedspectrum β-lactamases (ESBLs) being one of the most common. Carbapenems are currently used in the first-line treatment of serious infections caused by Gram-negative pathogens likely to produce ESBLs. However, resistance to these β-lactam antibiotics has been demonstrated, mediated by the production of carbapenemases such as Klebsiella pneumoniae carbapenemase.3 Widespread use Accepted for publication January 21, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.01.009 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics of carbapenems may lead to increased resistance in the future. Avibactam is a novel non–β-lactam β-lactamase inhibitor with in vitro activity against Ambler class A, C, and some class D β-lactamases, including K pneumoniae carbapenemase, AmpC, and ESBLs.4–6 Furthermore, avibactam is devoid of AmpC induction potential.7 The drug forms a stable covalent adduct with these βlactamases, resulting in inactivation,8 which gives avibactam the potential to be used in combination with β-lactam antibiotics to restore their activity against pathogen-resistant strains. Avibactam is currently in clinical development in combination with ceftazidime for the treatment of complicated intraabdominal and urinary tract infections and nosocomial pneumonia, and 2 Phase II studies have already been published (NCT00752219 and NCT00690 378).9,10 Avibactam is also being assessed in combination with ceftaroline fosamil5 and other β-lactams (eg, aztreonam).11 The safety, tolerability, pharmacokinetics, and pharmacodynamics of single, ascending intravenous doses of avibactam (as 30-minute infusions) have previously been studied in healthy young adult male subjects.12 Avibactam was administered either as a single agent (50–2000 mg) or as ceftazidime-avibactam combinations in a 4:1 dose ratio (1000:250 mg and 2000:500 mg). Avibactam, at doses up to 2000 mg, was well tolerated in this population, both systemically and locally, and drug exposure seemed to be proportional to dose. Avibactam is excreted largely unchanged in the urine.13 Because the pharmacokinetics and safety of medications may vary between male and female subjects, as well as between younger and older subjects,14,15 further investigation of avibactam pharmacokinetics was required for these different subgroups before advancing the ceftazidime-avibactam combination into clinical Phase II. The objective of the present study was to investigate the pharmacokinetics, safety, and tolerability of a single dose of avibactam in healthy young and elderly male and female volunteers. The dose of avibactam selected for investigation was based on the highest dose of avibactam planned for use in future therapeutic studies.
SUBJECTS AND METHODS This was a Phase I, open-label study (sponsor protocol number, NXL104-1004) conducted in healthy volunteers at a single center in the United States between
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February and October 2008. The study protocol was approved by an institutional review board (Chesapeake Research Review, Inc, Columbia, Maryland), and the study was conducted in accordance with Good Clinical Practice and sponsor standard operating procedures, which conform to the ethical principles of the Declaration of Helsinki. All subjects provided written informed consent.
Subjects Male and female volunteers were eligible for inclusion if they were aged Z18 years, in good health, had a body mass index 18 to 28 kg/m2 for young subjects (18–45 years) or 18 to 30 kg/m2 for elderly subjects (Z65 years), and systolic and diastolic blood pressures and heart rate were within the normal, agerelated ranges. Subjects were excluded if they had any condition requiring regular medication (unless approved by the sponsor); used any other over-thecounter or prescription medication within 14 days of study start; had a QTc interval Z420 milliseconds (4450 milliseconds in elderly subjects) or a pronounced sinus bradycardia (o40 beats/min), hypokalemia (o3.5 mEq/L), or family history of long QT syndrome, unexplained sudden death, sick sinus syndrome, or any clinically relevant cardiovascular disease; presence or sequelae of gastrointestinal, liver or kidney disease, or other conditions known to interfere with the distribution, metabolism, or excretion of drugs; evidence of HIV or hepatitis C infection; hematologic abnormalities (including white blood cell counts o3500/mm3, an absolute neutrophil count o1500/mm3, or a platelet count o100,000/mm3); creatinine 42 mg/dL; or evidence or history of drug abuse. Subjects were also excluded if they were a smoker of 45 cigarettes per day, a heavy caffeine drinker of >5 cups of coffee a day (or equivalent in xanthine-containing beverages), or whose intake of alcohol exceeded 2 units per day (or who were unwilling to stop alcohol consumption for the duration of the study). Male subjects had to be willing to abstain from sexual intercourse or use a condom/ spermicide for the duration of the study and for at least 90 days afterward. Female subjects of childbearing potential had to be willing to use doublebarrier methods of birth control. The volunteers were recruited into 1 of 4 cohorts: young male subjects (aged 18–45 years), young female subjects (aged 18–45 years), elderly male subjects (aged
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A. Tarral and H. Merdjan Z65 years), or elderly female subjects (aged Z65 years). Because this was the first study, to our knowledge, that evaluated the safety and tolerability of avibactam in elderly and female subjects, sample size was based on safety and pharmacokinetic results from a previous study assessing safety and pharmacokinetics in healthy male volunteers,12 as well as current standards for this type of investigation. Consequently, 8 subjects per cohort were to be included. On day 1, subjects were screened for eligibility to participate, and baseline measurements were recorded. Subjects received a single dose of the study drug on day 1 followed by 24 hours of postdose safety monitoring and pharmacokinetic sample collections. An end-of-study visit was performed 3 to 7 days after dosing. All subjects were contacted by telephone 14 days after dosing to assess the occurrence of adverse events (AEs).
Treatment Avibactam lyophilized powder (provided as a 1000-mg vial) was reconstituted in 10 mL of water for injection; 5 mL of the resultant 100-mg/mL solution was added to 95 mL of 5% glucose solution. Avibactam was then administered to all subjects as a single 500-mg dose by intravenous infusion given over 30 minutes. The concentration of the infused solution was therefore avibactam 5 mg/mL. This was administered on the morning of day 1 at least 30 minutes after breakfast. For young male and female subjects, no concomitant treatments were permitted for the duration of the study, except acetaminophen (r1000 mg/d) for the relief of headache. It was preferred that elderly male and female subjects also did not receive concomitant medications except acetaminophen (r1000 mg/d). Elderly subjects receiving stable chronic treatment were considered for enrollment on a case-by-case basis.
Pharmacokinetic Assessments Pharmacokinetic parameters were assessed in all subjects who received the full dose of study treatment and for whom pharmacokinetic data were considered interpretable by the sponsor. A total of 13 blood samples per subject were collected for pharmacokinetic analysis, starting before administration of avibactam and at 15, 30, and 45 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after the start of infusion.
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The blood samples (8 mL each) were collected into 2 separate 4-mL tubes (BD Vacutainer FX tubes, BD Diagnostics, Sparks Glencoe, Maryland) containing sodium fluoride (10 mg) and potassium oxalate (8 mg), and were immediately placed on ice. Plasma was obtained by centrifugation at 4oC and then frozen at approximately –70oC until pharmacokinetic analysis. Urine was collected on acetic acid predose and at 0 to 6, 6 to 12, and 12 to 24 hours postdose. Exact collection times and weights of urine were recorded. Two 10-mL aliquots from each sampling interval were stored at approximately –70oC until analysis by the central laboratory. The remaining urine was pooled to obtain a 0- to 24-hour sample, which was analyzed at the local laboratory to calculate creatinine clearance. Avibactam concentrations in plasma and urine samples were determined by using a validated bioanalytical assay with LC-MS/MS methods. The lower limits of quantification in plasma and urine were 0.01 and 0.1 mg/mL, respectively. Quality control (QC) samples were included in each analysis batch. The results of the QC samples were within the acceptance criteria, providing confidence in the bioanalytical data; that is, at least 75% of calibration samples were within ⫾15% (⫾20% at the lower limit of quantification) of their target concentration, and at least 4 of the 6 QC samples were within ⫾15% of their respective target values. In plasma QC samples, interbatch precision (%CV) for avibactam was 6.7% at the low QC level of 25 ng/mL, 5.6% at the medium QC level of 750 ng/mL, and 6.5% at the high QC level of 4000 ng/mL. In urine QC samples, interbatch precision (%CV) for avibactam was 6.0% at the low QC level of 25 ng/mL, 7.8% at the medium QC level of 750 ng/mL, and 6.8% at the high QC level of 4000 ng/mL. The pharmacokinetic parameters for plasma and urine were determined with WinNonlin Professional Edition version 5.1 (Pharsight Corporation, Mountain View, California) by using noncompartmental methods. Actual blood sampling times were used in all analyses. The following parameters were determined: Cmax, Tmax, AUC0–1 and AUC0–t, plasma clearance, t½, and apparent volume of distribution at steady state. Urinary excretion and recovery and renal clearance were also determined.
Safety Safety was assessed in all subjects who received any portion of the avibactam dose. Treatment-emergent
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Clinical Therapeutics AEs (defined as AEs occurring after informed consent had been given, before dosing but that worsened after dosing, and AEs that occurred after dosing) were coded by using version 10.1 of the Medical Dictionary for Regulatory Activities. Serious AEs were defined as those that resulted in death, were life-threatening, required hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or incapacity, were a congenital anomaly or birth defect, or were considered to be an important medical event. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) were conducted on blood and urine samples collected at screening, baseline (day before drug administration), 24-hour postdose, and at the end-of-study visit (on days 3–7). Vital signs (heart rate and blood pressure measured after 10 minutes of rest in the supine position and after Z3 minutes standing) were measured at regular intervals. In addition, 12-lead ECGs were recorded at screening, baseline (the day before treatment), predose, end of infusion, 1 hour after the start of the infusion, 24 hours after the start of the infusion, and at the end-of-study visit.
Statistical Analysis Descriptive statistics were used to express pharmacokinetic parameters according to cohort (including mean, SD, %CV, median, and range, as appropriate). Point estimates for the ratio of AUC0–1 and Cmax central values (elderly/nonelderly and male/female) were obtained by calculating the difference of least square means on the logarithmic scale and subsequent backtransformation with the antilog function. Likewise, 90% CIs for the ratios were obtained. All safety variables were listed by cohort, subject, and time point, with descriptive statistics according to cohort, as appropriate.
RESULTS Subjects Thirty-two subjects were initially enrolled in the study (8 in each treatment cohort). One subject in the young male cohort was lost to follow-up, and a replacement subject was therefore enrolled. Thirty-two subjects completed the study. Because the subject who was lost to follow-up had all the samples for pharmacokinetic assessment collected, this subject’s data are included in the pharmacokinetic and safety analyses. Baseline characteristics of the 4 cohorts are shown in Table I. The mean age of men and women were well matched within the 2 age categories (elderly and
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young). Most subjects in the elderly cohorts were white (Z75%), and most subjects in the young cohorts were black (Z62.5%). Concomitant medications for stable conditions were being taken by 4 subjects in the elderly cohorts; these were lisinopril 20 mg once daily by an elderly male subject; valsartan 80 mg once daily by an elderly male subject; aspirin 81 mg once daily and ibandronate 150 mg monthly by an elderly female subject; and valsartan hydrochlorothiazide 160/12.5 mg once daily and levothyroxine sodium 125 mg once daily by another elderly female subject. All of these concomitant medications were approved by the study sponsor.
Pharmacokinetic Evaluation All subjects had quantifiable avibactam concentrations postdose. The figure presents mean avibactam plasma concentration over time for each cohort. In all 4 cohorts, the plasma concentration of avibactam peaked rapidly at 30 to 60 minutes after the start of the infusion of avibactam, followed by a rapid biphasic decline. In general, avibactam remained measurable in the plasma of the elderly population for longer than in the young population. All young subjects had quantifiable plasma concentrations up to the 12-hour postdose time point, but only 2 young subjects (both male) had quantifiable plasma concentrations up to the 24-hour postdose time point. Most elderly subjects (8 men, 5 women) had quantifiable plasma concentrations up to the 24-hour time point. Mean Cmax was similar in the young male, young female, and elderly female cohorts (33.83, 36.86, and 38.41 mg/mL, respectively) but was lower in the elderly male cohort (26.45 mg/mL) (Table II). Analysis of the effects of sex and age showed that male subjects, on average, had 18% lower Cmax values than female subjects (90% CI, 30% to 5% lower), and elderly subjects, on average, had 12% lower Cmax than young subjects (90% CI, 24% lower to 2% higher). Mean AUC0–1 was similar between the young male, young female, and elderly male cohorts, and it was higher for the elderly female cohort. Analysis according to age and sex showed that AUC0–1 values were, on average, 17% higher in elderly subjects compared with young subjects (90% CI, 5% to 31% higher), and 10% lower in male subjects compared with female subjects (90% CI, 20% lower to no difference). Similar trends were
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Table I. Subject demographic and baseline clinical characteristics. Unless otherwise stated, data are mean (SD).
Characteristic Age, y Height, cm Weight, kg Body mass index, kg/m2 Creatinine clearance, mL/min* Race, no. (%) Black or African American White Ethnicity, n (%) Hispanic or Latino Non-Hispanic or Latino *
Young Male Subjects: 18–45 y (n ¼ 9) 28.7 177.6 77.0 24.4 114.3
(6.0) (6.5) (9.0) (2.4) (23.0)
Young Female Subjects: 18–45 y (n ¼ 8) 30.9 162.6 61.4 23.1 99.0
(6.8) (5.3) (11.4) (3.3) (14.7)
Elderly Male Subjects: Z65 y (n ¼ 8) 68.8 177.4 82.2 26.1 77.1
(3.4) (3.5) (11.2) (3.2) (11.7)
Elderly Female Subjects: Z65 y (n ¼ 8) 69.1 162.3 67.4 25.5 72.3
(3.6) (4.5) (11.6) (3.4) (20.0)
6 (66.7) 3 (33.3)
5 (62.5) 3 (37.5)
1 (12.5) 7 (87.5)
2 (25.0) 6 (75.0)
3 (33.3) 6 (66.7)
0 8 (100.0)
0 8 (100.0)
0 8 (100.0)
Estimated by using the Cockroft-Gault formula.
observed for AUC0–t. The intersubject variability was low for AUC0–t and AUC0–1 in all cohorts (%CV range, 12.6%–23.3%). The mean t½ of avibactam ranged from 1.71 to 3.12 hours in the 4 cohorts, with a tendency to be slightly longer for the elderly cohorts compared with the young cohorts (Table II). Mean plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and it was slightly lower for the elderly female cohort (7.98 L/h). Mean urinary recovery over 24 hours (ie, the percentage of avibactam dose recovered in the urine) was higher for young male and female subjects (91.45% and 85.91%, respectively) compared with elderly male and female subjects (67.89% and 59.73%) (Table II). In 8 (24%) of 33 subjects, 4100% of the avibactam dose was recovered in the urine (maximum 140% of the dose). Renal clearance of avibactam was also higher for young male and female subjects (9.23 and 8.62 L/h) compared with elderly male and female subjects (6.93 and 4.51 L/h).
Safety Twenty treatment-emergent AEs were reported by 11 subjects (Table III). More AEs were reported by
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women of any age (17 events reported by 8 female subjects, of which 4 events were reported in a single elderly woman) compared with male subjects (3 events reported by 3 male subjects). All AEs were of mild intensity and resolved by the end of the study. There were no deaths or serious AEs. The most commonly reported AEs were administration/venipuncture site bruising in 4 subjects. Adverse events considered possibly related to study medication occurred in 1 young male subject (mild headache) and 2 elderly female subjects (1 subject experienced arthralgia, feeling jittery, feeling hot, and hyperhidrosis, and 1 subject experienced dry mouth and dysgeusia). There were no clinically significant changes in biochemistry, hematology, or urinalysis values or ECG measurements in any cohort.
DISCUSSION
This study was the first to investigate the effect of age and sex on the pharmacokinetics, safety, and tolerability profile of avibactam. In general, avibactam pharmacokinetics were similar in young male and female subjects. Although there were trends for some differences in pharmacokinetics between the young and elderly subjects and between the elderly male and female subjects, these were not considered sufficient to
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Clinical Therapeutics
Avibactam Plasma Concentration (µg/mL)
A Young men Young women Elderly men Elderly women
55 50 45 40 35 30 25 20 15 10 5 0 0
2
4
6
Time (h)
Avibactam Plasma Concentration (µg/mL)
B
Young men Young women Elderly men Elderly women
55 50 45 40 35 30 25 20 15 10 5 0 0
2
4
6
8 10 12 14 16 18 20 22 24 Time (h)
Figure. Mean (SD) avibactam plasma concentrations over (A) the first 6 hours and (B) 24 hours.
warrant dose adjustment in clinical practice. Cmax was broadly comparable across cohorts but was slightly lower for elderly male subjects. Mean creatinine clearance (CrCL) values were numerically different across cohorts, with young subjects exhibiting higher values than elderly subjects (as expected). Because renal excretion is the main elimination pathway of avibactam,12,13 differences in CrCL affect renal clearance values; these values were somewhat lower in elderly men (6.93 L/h), and lower still in elderly women (4.51 L/h), than in young male and female subjects (9.23 and 8.62 L/h, respectively). This provides a plausible mechanistic explanation for the apparent age-related change in AUC, with mean
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AUC being comparable in young male subjects and in female and elderly male subjects, but greater in elderly female subjects. The reason for the lower renal excretion in elderly women than in elderly men does not seem to be related to differences in CrCL alone, but it is not anticipated to have a clinically significant impact on exposure to avibactam. In both elderly male and female subjects, plasma levels of avibactam were detectable for longer and the t½ was longer than in younger subjects, which may be partly due to the reduced renal function generally observed in elderly subjects. Furthermore, least squares mean Cmax was 12% lower (90% CI, 24% lower to 2% higher) and least squares mean AUC0-1 was 17% higher (90% CI, 5% to 31% higher) in the elderly cohort compared with the young cohort. Overall, these findings suggest a potential for somewhat higher exposure in the elderly. However, there was considerable overlap between the 4 cohorts in the range of values for AUC0-inf (lowest mean value 49.75 μg h/mL in young women; highest mean value 66.23 μg h/mL in elderly women) and Cmax (lowest mean value 26.45 μg/mL in elderly males and highest mean value 38.41 μg/mL in elderly females). In addition, based on the moderate nature of the difference in magnitude between groups in exposure, a dose adjustment is not warranted in the elderly. We showed that avibactam underwent predominantly renal excretion, with a mean of 91% and 86% of the dose recovered in urine within 24 hours of administration in the young male and female cohorts, respectively. Urinary excretion in the first 24 hours after dosing was lower in the elderly cohorts (68% in elderly men and 60% in elderly women), possibly reflecting age-related differences in renal function. Although these results confirm earlier findings that avibactam excretion is primarily via the renal route,12,13 it should be noted that in 8 patients, urinary recovery was 4100% (maximum recovery was 140% in 1 patient). These results may be due to inaccuracy in recording the volume of urinary sampling or the propagation of individual errors when deriving cumulative recovery data. In addition, avibactam was shown to be generally well tolerated in the healthy volunteers in this study. Overall, AEs were reported by 11 (33%) subjects who experienced a total of 20 events. Although more AEs were reported by female subjects (particularly in 1 elderly woman who reported 4 adverse events) than
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Table II. Pharmacokinetic parameters. Unless otherwise stated, values are arithmetic mean (%CV). Pharmacokinetic parameter Cmax, mg/mL Tmax, h* T0–last, h* t1/2, h Plasma clearance, L/h Vss, L AUC0-t, μg h/mL AUC0–inf, μg h/mL Urinary excretion (% of dose in 24 hours) CLR over 0–24 hours, L/h†
Young Male Subjects: 18–45 y (n ¼ 9) 33.83 0.52 12.00 2.09 10.16 16.84 49.65 49.86 91.45
(12.52) (0.50–0.75) (11.98–24.08) (30.38) (12.10) (15.43) (12.57) (12.57) (41.63)
9.23 (67.56)
Young Female Subjects: 18–45 y (n ¼ 8) 36.86 0.50 12.00 1.71 10.34 15.20 49.59 49.75 85.91
(25.25) (0.50–0.75) (12.00–12.03) (5.22) (17.64) (24.12) (18.31) (18.28) (26.62)
8.62 (18.44)
Elderly Male Subjects: Z65 y (n ¼ 8) 26.45 0.50 24.03 3.17 9.82 24.29 52.29 52.40 67.89
(21.67) (0.50–1.00) (23.95–24.15) (20.65) (18.47) (24.15) (17.99) (17.90) (33.01)
6.93 (47.21)
Elderly Female Subjects: Z65 y (n ¼ 8) 38.41 0.50 24.03 2.43 7.98 16.72 65.90 66.23 59.73
(40.39) (0.50–0.53) (7.97–24.15) (19.29) (27.80) (26.48) (23.33) (22.60) (45.49)
4.51 (35.97)
CL ¼ plasma clearance; t1/2 ¼ terminal half-life; T0–last ¼ time of last quantifiable concentration; Vss ¼ apparent volume of distribution at steady state; CLR ¼ renal clearance. * Median (range). † %CV values for CLR were calculated using log-transformed data.
by male subjects, all AEs were of mild intensity and resolved by the end of the study. The most commonly reported AE was administration/venipuncture site bruising; all other AEs were isolated reports. Three subjects experienced AEs considered possibly related to the study drug: headache in 1 male subject; arthralgia, feeling jittery, feeling hot, and hyperhidrosis in 1 female subject; and dry mouth and dysgeusia in another female subject. The results of the present study confirm the results of a previous study evaluating the safety, tolerability, and pharmacokinetics of single, ascending doses of avibactam (50–2000 mg) in 70 healthy male subjects.12 Over the dose range, mean plasma clearance ranged from 10.4 to 13.8 L/h, volume of distribution from 19.5 to 24.3 L, and t½ from 1.5 to 2.7 hours. By way of comparison, in young male subjects in our study receiving avibactam 500 mg, mean plasma clearance was 10.16 L/h, volume of distribution was 16.8 L, and t½ was 2.09 hours; these findings were similar to the previous study. Avibactam pharmacokinetics were shown to be linear over the whole dose range (50–2000 mg), and avibactam was well tolerated in the previous study as well.
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The generalizability of the present study is limited due to the small sample size (33 subjects across 4 cohorts). Nevertheless, the small differences noted in AUC between the age cohorts in the present study are not sufficient to warrant dose adjustments in elderly subjects. However, as would be expected based on the predominantly renal excretion of avibactam, previous studies suggest that dose adjustments are required in subjects with renal impairment.16,17 In addition, the present study did not stratify patients according to race or ethnicity, and there was a disparity between groups in this regard (Table I). Studies to investigate the influence of race on the safety and pharmacokinetics of avibactam have recently been completed in Chinese and Japanese populations (NCT01920399 and NCT01291602, respectively). The choice of the 500-mg avibactam dose used in the present study was based on safety and tolerability data obtained in the single ascending dose study12 and is an appropriate dose of avibactam based on in vitro susceptibility testing, hollow fiber experiments, and preclinical data.18–21 In addition, avibactam 500 mg is the therapeutic dose being used in ongoing and recently completed Phase III clinical studies (NCT01726023, NCT01499290, NCT01500239,
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Clinical Therapeutics
Table III. Treatment-emergent adverse events (AEs) (no. [%]) regardless of perceived relationship to study drug (safety population).
AE Subjects with any AE Total no. of AEs observed Individual AEs observed Administration site bruising Venipuncture site bruising Headache Arthralgia Chest discomfort Cough Diarrhea Dry mouth Dysgeusia Fatigue Feeling hot Feeling jittery Hyperhidrosis Upper respiratory tract infection
Young Male Subjects: 18–45 y (n ¼ 9)
Young Female Subjects: 18–45 y (n ¼ 8)
Elderly Male Subjects: Z65 y Elderly Female Subjects (n ¼ 8) Z65 y (n ¼ 8)
1 (11.1) 1
3 (37.5) 7
2 (25.0) 2
5 (62.5) 10
0
1 (12.5)a
1 (12.5)
1 (12.5)b
0
1 (12.5)a
1 (12.5)
1 (12.5)b
1 (11.1)* 0 0 0 0 0 0 0 0 0 0 0
1 (12.5)a 0 1 (12.5)c 1 (12.5)c 1 (12.5)c 0 0 0 0 0 0 1 (12.5)
0 0 0 0 0 0 0 0 0 0 0 0
0 1 (12.5)d 0 0 1 (12.5) 1 (12.5)e* 1 (12.5)e* 1 (12.5) 1 (12.5)d* 1 (12.5)d* 1 (12.5)d* 0
Note: Letters “a” to “e” denote multiple AEs occurring in a single subject. * AEs considered possibly related to study medication. These were recorded in 1 young male subject and 2 elderly female subjects overall.
NCT01595438, NCT01599806, NCT01808092, and NCT01644643). Avibactam is currently being studied clinically in combination with ceftazidime and ceftaroline fosamil, and it may potentially be evaluated with other β-lactams, to determine whether it restores the activity of these antimicrobial agents against resistant Gramnegative bacterial pathogens. The results of a single ascending dose study in healthy male volunteers suggested that the pharmacokinetic parameters of avibactam are similar, whether given alone or in combination with ceftazidime.12 When tested against ESBL-producing Escherichia coli and K pneumoniae
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isolates, avibactam restored susceptibility to ceftazidime and several other cephalosporin antibiotics for all isolates tested.22
CONCLUSIONS Avibactam was generally well tolerated in the healthy young and elderly male and female cohorts in the present study. There were no notable differences in pharmacokinetic parameters between the male and female cohorts. The small differences in pharmacokinetic parameters between the young and elderly cohorts are not sufficient to warrant dose adjustments based on age beyond that necessary due to reduced renal function.
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ACKNOWLEDGMENTS The authors thank Joy Lipka and Carole Sable (formerly of Novexel); Shwe Gyaw, Pepi Pencheva, and Rachel Garner (formerly of Parexel International); and Walter Heber (Parexel International) for their contributions to the study. Pepi Pencheva is currently at DP Clinical, Inc. This study was led by Novexel. Ceftazidimeavibactam is currently being developed by AstraZeneca and Forest-Cerexa, now a subsidiary of Actavis. Medical writing support was provided by Caroline Shapland, and editorial support was provided by Liz Anfield and Catherine Savage, all of Prime Medica Ltd, Knutsford, Cheshire funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.
CONFLICTS OF INTEREST A. Tarral and H. Merdjan were employees of Novexel SA at the time of conduct of the studies. The study sponsor was involved in the study design, collection, analysis, and interpretation of the data.
REFERENCES 1. Peleg AY, Hooper DC. Hospital-acquired infections due to Gram-negative bacteria. N Engl J Med. 2010;362:1804–1813. 2. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant Gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011;86:250–259. 3. Nordmann P, Nass T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011;17:1791–1798. 4. Stachyra T, et al. In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009;64:326–329. 5. Castanheira M, Sader HS, Farrell DJ, et al. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother. 2012;56:4779–4785. 6. Livermore DM, Mushtaq S, Warner M, et al. NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. J Antimicrob Chemother. 2008;62:1053–1056.
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7. Miossec C, Claudon M, Levasseur P, Black MT. The β-lactamase inhibitor avibactam (NXL104) does not induce ampC β-lactamase in Enterobacter cloacae. Infect Drug Resist. 2013;6:235–240. 8. Stachyra T, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010; 54:5132–5138. 9. Lucasti C, Popescu I, Ramesh M, et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68:1183–1192. 10. Vazquez JA, et al. Efficacy and safety of ceftazidimeavibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28:1921–1931. 11. Livermore DM, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemaseproducing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55:390–394. 12. Merdjan, H. et al. Safety, single dose pharmacokinetics, and pharmacodynamics of beta-lactamase inhibitor NXL104 in healthy young male adults. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois (2007). Abstract A-809. 13. Vishwanathan K, et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos. 2014;42:932–942. 14. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57:6–14. 15. Whitley H, Lindsey W. Sex-based differences in drug activity. Am Fam Physician. 2009;80:1254–1258. 16. Felices M, Gualano V, Tarral A, et al. Combined population pharmacokinetic analysis of four phase 1 studies with NXL104. 20th European Congress of Clinical Microbiology and Infectious Diseases Vienna, Austria (2010). Abstract P1599. 17. Merdjan H, Tarral A, Haazen W, et al. Pharmacokinetics and tolerability of NXL104 in normal subjects and patients with varying degrees of renal insufficiency. (Abstract P1598). Clin Microbiol Infect. 2010;16:S465. 18. Levasseur, P. et al. NXL104, a novel β-lactamase inhibitor, restores the bactericidal activity of ceftazidime against ESBL and AmpC producing strains of Enterobacteriaceae. 46th International Conference on Antimicrobial Agents and Chemotherapy San Francisco, California (2006). Abstract F127.
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Clinical Therapeutics 19. Coleman K, et al. Activities of ceftazidime and avibactam against β-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob Agents Chemother. 2014;58:3366–3372. 20. Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases. Antimicrob Agents Chemother. 2009;53: 3599–3601. 21. Endimiani A, Hujer KM, Hujer AM, et al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55:82–85. 22. Lagacé-Wiens PR, et al. Activity of NXL104 in combination with β-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing Class A extended-spectrum beta-lactamases and Class C beta-lactamases. Antimicrob Agents Chemother. 2011;55:2434–2437.
Address correspondence to: Antoine Tarral, MD, DNDi Drugs for Neglected Diseases Initiative, 15 chemin Louis-Dunant, 1202 Geneva, Switzerland. E-mail: [email protected]
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Effect of Age and Sex on the Pharmacokinetics and Safety of Avibactam in Healthy Volunteers Antoine Tarral, MD*; and Henri Merdjan, PharmD† Formerly of Novexel SA, Romainville, France ABSTRACT Purpose: Avibactam is a novel non–β-lactam β-lactamase inhibitor currently being assessed in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The objectives of this study were to investigate the pharmacokinetics, safety, and tolerability of avibactam in healthy young (aged 18–45 years) and elderly (aged Z65 years) volunteers of both sexes. Methods: This was a Phase I, open-label study in which healthy volunteers aged Z18 years were enrolled into 4 cohorts: young male, young female, elderly male, and elderly female (n ¼ 8 in each group). Subjects were excluded if they had any condition requiring regular medication or any other relevant conditions. All subjects received a single dose of avibactam 500 mg/100 mL given intravenously over 30 minutes. Pharmacokinetic measurements included Cmax, Tmax, AUC0–1, plasma clearance, and t½. Findings: Within the two age categories the mean age across male and female subjects was well matched. The majority of subjects in the young cohort were black (≥62.5%), whilst the majority of those in the elderly cohorts were white (≥75%). Mean avibactam plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and slightly lower in elderly women (7.98 L/h). Mean Cmax was similar in young male, young female, and elderly female subjects (33.8, 36.9, and 38.4 mg/mL) but lower in elderly male subjects (26.5 mg/mL). Point estimates comparing the ratio of Cmax in male and female subjects over all age groups suggested that Cmax values were 18% lower (90% CI, 30%–5% lower) in male subjects compared with female subjects. Mean AUC0–1 data were similar between the young male, *
Current affiliation: DNDi Drugs for Neglected Diseases Initiative, Geneva, Switzerland. † Current affiliation: Pharsight Consulting Services Europe, Paris, France.
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young female, and elderly male cohorts (49.86, 49.75, and 52.40 mg h/mL) but higher in elderly women (66.23 mg h/mL). Point estimates comparing the ratio of AUC0–1 in elderly and young subjects across both sexes suggested that AUC0–1 values were 17% higher (90% CI, 5%–31%) in elderly subjects compared with young subjects. The t½ was slightly longer for elderly subjects compared with younger subjects. The most common adverse event was administration/venipuncture site bruising (6 events); all adverse events were mild. Implications: No notable differences in pharmacokinetics were observed between the male and female cohorts. The generalizability of the study is limited due to its small sample size. However, the small differences observed between the young and elderly cohorts are not sufficient to warrant dosing adjustments based on age. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: age, avibactam, pharmacokinetics, sex.
INTRODUCTION Gram-negative pathogens are responsible for a large proportion of nosocomial infections,1 as well as those acquired in the community. Gram-negative organisms have developed highly efficient mechanisms for antibiotic drug resistance,2 with the production of extendedspectrum β-lactamases (ESBLs) being one of the most common. Carbapenems are currently used in the first-line treatment of serious infections caused by Gram-negative pathogens likely to produce ESBLs. However, resistance to these β-lactam antibiotics has been demonstrated, mediated by the production of carbapenemases such as Klebsiella pneumoniae carbapenemase.3 Widespread use Accepted for publication January 21, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.01.009 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics of carbapenems may lead to increased resistance in the future. Avibactam is a novel non–β-lactam β-lactamase inhibitor with in vitro activity against Ambler class A, C, and some class D β-lactamases, including K pneumoniae carbapenemase, AmpC, and ESBLs.4–6 Furthermore, avibactam is devoid of AmpC induction potential.7 The drug forms a stable covalent adduct with these βlactamases, resulting in inactivation,8 which gives avibactam the potential to be used in combination with β-lactam antibiotics to restore their activity against pathogen-resistant strains. Avibactam is currently in clinical development in combination with ceftazidime for the treatment of complicated intraabdominal and urinary tract infections and nosocomial pneumonia, and 2 Phase II studies have already been published (NCT00752219 and NCT00690 378).9,10 Avibactam is also being assessed in combination with ceftaroline fosamil5 and other β-lactams (eg, aztreonam).11 The safety, tolerability, pharmacokinetics, and pharmacodynamics of single, ascending intravenous doses of avibactam (as 30-minute infusions) have previously been studied in healthy young adult male subjects.12 Avibactam was administered either as a single agent (50–2000 mg) or as ceftazidime-avibactam combinations in a 4:1 dose ratio (1000:250 mg and 2000:500 mg). Avibactam, at doses up to 2000 mg, was well tolerated in this population, both systemically and locally, and drug exposure seemed to be proportional to dose. Avibactam is excreted largely unchanged in the urine.13 Because the pharmacokinetics and safety of medications may vary between male and female subjects, as well as between younger and older subjects,14,15 further investigation of avibactam pharmacokinetics was required for these different subgroups before advancing the ceftazidime-avibactam combination into clinical Phase II. The objective of the present study was to investigate the pharmacokinetics, safety, and tolerability of a single dose of avibactam in healthy young and elderly male and female volunteers. The dose of avibactam selected for investigation was based on the highest dose of avibactam planned for use in future therapeutic studies.
SUBJECTS AND METHODS This was a Phase I, open-label study (sponsor protocol number, NXL104-1004) conducted in healthy volunteers at a single center in the United States between
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February and October 2008. The study protocol was approved by an institutional review board (Chesapeake Research Review, Inc, Columbia, Maryland), and the study was conducted in accordance with Good Clinical Practice and sponsor standard operating procedures, which conform to the ethical principles of the Declaration of Helsinki. All subjects provided written informed consent.
Subjects Male and female volunteers were eligible for inclusion if they were aged Z18 years, in good health, had a body mass index 18 to 28 kg/m2 for young subjects (18–45 years) or 18 to 30 kg/m2 for elderly subjects (Z65 years), and systolic and diastolic blood pressures and heart rate were within the normal, agerelated ranges. Subjects were excluded if they had any condition requiring regular medication (unless approved by the sponsor); used any other over-thecounter or prescription medication within 14 days of study start; had a QTc interval Z420 milliseconds (4450 milliseconds in elderly subjects) or a pronounced sinus bradycardia (o40 beats/min), hypokalemia (o3.5 mEq/L), or family history of long QT syndrome, unexplained sudden death, sick sinus syndrome, or any clinically relevant cardiovascular disease; presence or sequelae of gastrointestinal, liver or kidney disease, or other conditions known to interfere with the distribution, metabolism, or excretion of drugs; evidence of HIV or hepatitis C infection; hematologic abnormalities (including white blood cell counts o3500/mm3, an absolute neutrophil count o1500/mm3, or a platelet count o100,000/mm3); creatinine 42 mg/dL; or evidence or history of drug abuse. Subjects were also excluded if they were a smoker of 45 cigarettes per day, a heavy caffeine drinker of >5 cups of coffee a day (or equivalent in xanthine-containing beverages), or whose intake of alcohol exceeded 2 units per day (or who were unwilling to stop alcohol consumption for the duration of the study). Male subjects had to be willing to abstain from sexual intercourse or use a condom/ spermicide for the duration of the study and for at least 90 days afterward. Female subjects of childbearing potential had to be willing to use doublebarrier methods of birth control. The volunteers were recruited into 1 of 4 cohorts: young male subjects (aged 18–45 years), young female subjects (aged 18–45 years), elderly male subjects (aged
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A. Tarral and H. Merdjan Z65 years), or elderly female subjects (aged Z65 years). Because this was the first study, to our knowledge, that evaluated the safety and tolerability of avibactam in elderly and female subjects, sample size was based on safety and pharmacokinetic results from a previous study assessing safety and pharmacokinetics in healthy male volunteers,12 as well as current standards for this type of investigation. Consequently, 8 subjects per cohort were to be included. On day 1, subjects were screened for eligibility to participate, and baseline measurements were recorded. Subjects received a single dose of the study drug on day 1 followed by 24 hours of postdose safety monitoring and pharmacokinetic sample collections. An end-of-study visit was performed 3 to 7 days after dosing. All subjects were contacted by telephone 14 days after dosing to assess the occurrence of adverse events (AEs).
Treatment Avibactam lyophilized powder (provided as a 1000-mg vial) was reconstituted in 10 mL of water for injection; 5 mL of the resultant 100-mg/mL solution was added to 95 mL of 5% glucose solution. Avibactam was then administered to all subjects as a single 500-mg dose by intravenous infusion given over 30 minutes. The concentration of the infused solution was therefore avibactam 5 mg/mL. This was administered on the morning of day 1 at least 30 minutes after breakfast. For young male and female subjects, no concomitant treatments were permitted for the duration of the study, except acetaminophen (r1000 mg/d) for the relief of headache. It was preferred that elderly male and female subjects also did not receive concomitant medications except acetaminophen (r1000 mg/d). Elderly subjects receiving stable chronic treatment were considered for enrollment on a case-by-case basis.
Pharmacokinetic Assessments Pharmacokinetic parameters were assessed in all subjects who received the full dose of study treatment and for whom pharmacokinetic data were considered interpretable by the sponsor. A total of 13 blood samples per subject were collected for pharmacokinetic analysis, starting before administration of avibactam and at 15, 30, and 45 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after the start of infusion.
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The blood samples (8 mL each) were collected into 2 separate 4-mL tubes (BD Vacutainer FX tubes, BD Diagnostics, Sparks Glencoe, Maryland) containing sodium fluoride (10 mg) and potassium oxalate (8 mg), and were immediately placed on ice. Plasma was obtained by centrifugation at 4oC and then frozen at approximately –70oC until pharmacokinetic analysis. Urine was collected on acetic acid predose and at 0 to 6, 6 to 12, and 12 to 24 hours postdose. Exact collection times and weights of urine were recorded. Two 10-mL aliquots from each sampling interval were stored at approximately –70oC until analysis by the central laboratory. The remaining urine was pooled to obtain a 0- to 24-hour sample, which was analyzed at the local laboratory to calculate creatinine clearance. Avibactam concentrations in plasma and urine samples were determined by using a validated bioanalytical assay with LC-MS/MS methods. The lower limits of quantification in plasma and urine were 0.01 and 0.1 mg/mL, respectively. Quality control (QC) samples were included in each analysis batch. The results of the QC samples were within the acceptance criteria, providing confidence in the bioanalytical data; that is, at least 75% of calibration samples were within ⫾15% (⫾20% at the lower limit of quantification) of their target concentration, and at least 4 of the 6 QC samples were within ⫾15% of their respective target values. In plasma QC samples, interbatch precision (%CV) for avibactam was 6.7% at the low QC level of 25 ng/mL, 5.6% at the medium QC level of 750 ng/mL, and 6.5% at the high QC level of 4000 ng/mL. In urine QC samples, interbatch precision (%CV) for avibactam was 6.0% at the low QC level of 25 ng/mL, 7.8% at the medium QC level of 750 ng/mL, and 6.8% at the high QC level of 4000 ng/mL. The pharmacokinetic parameters for plasma and urine were determined with WinNonlin Professional Edition version 5.1 (Pharsight Corporation, Mountain View, California) by using noncompartmental methods. Actual blood sampling times were used in all analyses. The following parameters were determined: Cmax, Tmax, AUC0–1 and AUC0–t, plasma clearance, t½, and apparent volume of distribution at steady state. Urinary excretion and recovery and renal clearance were also determined.
Safety Safety was assessed in all subjects who received any portion of the avibactam dose. Treatment-emergent
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Clinical Therapeutics AEs (defined as AEs occurring after informed consent had been given, before dosing but that worsened after dosing, and AEs that occurred after dosing) were coded by using version 10.1 of the Medical Dictionary for Regulatory Activities. Serious AEs were defined as those that resulted in death, were life-threatening, required hospitalization or prolonged existing hospitalization, resulted in persistent or significant disability or incapacity, were a congenital anomaly or birth defect, or were considered to be an important medical event. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) were conducted on blood and urine samples collected at screening, baseline (day before drug administration), 24-hour postdose, and at the end-of-study visit (on days 3–7). Vital signs (heart rate and blood pressure measured after 10 minutes of rest in the supine position and after Z3 minutes standing) were measured at regular intervals. In addition, 12-lead ECGs were recorded at screening, baseline (the day before treatment), predose, end of infusion, 1 hour after the start of the infusion, 24 hours after the start of the infusion, and at the end-of-study visit.
Statistical Analysis Descriptive statistics were used to express pharmacokinetic parameters according to cohort (including mean, SD, %CV, median, and range, as appropriate). Point estimates for the ratio of AUC0–1 and Cmax central values (elderly/nonelderly and male/female) were obtained by calculating the difference of least square means on the logarithmic scale and subsequent backtransformation with the antilog function. Likewise, 90% CIs for the ratios were obtained. All safety variables were listed by cohort, subject, and time point, with descriptive statistics according to cohort, as appropriate.
RESULTS Subjects Thirty-two subjects were initially enrolled in the study (8 in each treatment cohort). One subject in the young male cohort was lost to follow-up, and a replacement subject was therefore enrolled. Thirty-two subjects completed the study. Because the subject who was lost to follow-up had all the samples for pharmacokinetic assessment collected, this subject’s data are included in the pharmacokinetic and safety analyses. Baseline characteristics of the 4 cohorts are shown in Table I. The mean age of men and women were well matched within the 2 age categories (elderly and
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young). Most subjects in the elderly cohorts were white (Z75%), and most subjects in the young cohorts were black (Z62.5%). Concomitant medications for stable conditions were being taken by 4 subjects in the elderly cohorts; these were lisinopril 20 mg once daily by an elderly male subject; valsartan 80 mg once daily by an elderly male subject; aspirin 81 mg once daily and ibandronate 150 mg monthly by an elderly female subject; and valsartan hydrochlorothiazide 160/12.5 mg once daily and levothyroxine sodium 125 mg once daily by another elderly female subject. All of these concomitant medications were approved by the study sponsor.
Pharmacokinetic Evaluation All subjects had quantifiable avibactam concentrations postdose. The figure presents mean avibactam plasma concentration over time for each cohort. In all 4 cohorts, the plasma concentration of avibactam peaked rapidly at 30 to 60 minutes after the start of the infusion of avibactam, followed by a rapid biphasic decline. In general, avibactam remained measurable in the plasma of the elderly population for longer than in the young population. All young subjects had quantifiable plasma concentrations up to the 12-hour postdose time point, but only 2 young subjects (both male) had quantifiable plasma concentrations up to the 24-hour postdose time point. Most elderly subjects (8 men, 5 women) had quantifiable plasma concentrations up to the 24-hour time point. Mean Cmax was similar in the young male, young female, and elderly female cohorts (33.83, 36.86, and 38.41 mg/mL, respectively) but was lower in the elderly male cohort (26.45 mg/mL) (Table II). Analysis of the effects of sex and age showed that male subjects, on average, had 18% lower Cmax values than female subjects (90% CI, 30% to 5% lower), and elderly subjects, on average, had 12% lower Cmax than young subjects (90% CI, 24% lower to 2% higher). Mean AUC0–1 was similar between the young male, young female, and elderly male cohorts, and it was higher for the elderly female cohort. Analysis according to age and sex showed that AUC0–1 values were, on average, 17% higher in elderly subjects compared with young subjects (90% CI, 5% to 31% higher), and 10% lower in male subjects compared with female subjects (90% CI, 20% lower to no difference). Similar trends were
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A. Tarral and H. Merdjan
Table I. Subject demographic and baseline clinical characteristics. Unless otherwise stated, data are mean (SD).
Characteristic Age, y Height, cm Weight, kg Body mass index, kg/m2 Creatinine clearance, mL/min* Race, no. (%) Black or African American White Ethnicity, n (%) Hispanic or Latino Non-Hispanic or Latino *
Young Male Subjects: 18–45 y (n ¼ 9) 28.7 177.6 77.0 24.4 114.3
(6.0) (6.5) (9.0) (2.4) (23.0)
Young Female Subjects: 18–45 y (n ¼ 8) 30.9 162.6 61.4 23.1 99.0
(6.8) (5.3) (11.4) (3.3) (14.7)
Elderly Male Subjects: Z65 y (n ¼ 8) 68.8 177.4 82.2 26.1 77.1
(3.4) (3.5) (11.2) (3.2) (11.7)
Elderly Female Subjects: Z65 y (n ¼ 8) 69.1 162.3 67.4 25.5 72.3
(3.6) (4.5) (11.6) (3.4) (20.0)
6 (66.7) 3 (33.3)
5 (62.5) 3 (37.5)
1 (12.5) 7 (87.5)
2 (25.0) 6 (75.0)
3 (33.3) 6 (66.7)
0 8 (100.0)
0 8 (100.0)
0 8 (100.0)
Estimated by using the Cockroft-Gault formula.
observed for AUC0–t. The intersubject variability was low for AUC0–t and AUC0–1 in all cohorts (%CV range, 12.6%–23.3%). The mean t½ of avibactam ranged from 1.71 to 3.12 hours in the 4 cohorts, with a tendency to be slightly longer for the elderly cohorts compared with the young cohorts (Table II). Mean plasma clearance was similar between the young male, young female, and elderly male cohorts (10.16, 10.34, and 9.82 L/h, respectively), and it was slightly lower for the elderly female cohort (7.98 L/h). Mean urinary recovery over 24 hours (ie, the percentage of avibactam dose recovered in the urine) was higher for young male and female subjects (91.45% and 85.91%, respectively) compared with elderly male and female subjects (67.89% and 59.73%) (Table II). In 8 (24%) of 33 subjects, 4100% of the avibactam dose was recovered in the urine (maximum 140% of the dose). Renal clearance of avibactam was also higher for young male and female subjects (9.23 and 8.62 L/h) compared with elderly male and female subjects (6.93 and 4.51 L/h).
Safety Twenty treatment-emergent AEs were reported by 11 subjects (Table III). More AEs were reported by
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women of any age (17 events reported by 8 female subjects, of which 4 events were reported in a single elderly woman) compared with male subjects (3 events reported by 3 male subjects). All AEs were of mild intensity and resolved by the end of the study. There were no deaths or serious AEs. The most commonly reported AEs were administration/venipuncture site bruising in 4 subjects. Adverse events considered possibly related to study medication occurred in 1 young male subject (mild headache) and 2 elderly female subjects (1 subject experienced arthralgia, feeling jittery, feeling hot, and hyperhidrosis, and 1 subject experienced dry mouth and dysgeusia). There were no clinically significant changes in biochemistry, hematology, or urinalysis values or ECG measurements in any cohort.
DISCUSSION
This study was the first to investigate the effect of age and sex on the pharmacokinetics, safety, and tolerability profile of avibactam. In general, avibactam pharmacokinetics were similar in young male and female subjects. Although there were trends for some differences in pharmacokinetics between the young and elderly subjects and between the elderly male and female subjects, these were not considered sufficient to
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Clinical Therapeutics
Avibactam Plasma Concentration (µg/mL)
A Young men Young women Elderly men Elderly women
55 50 45 40 35 30 25 20 15 10 5 0 0
2
4
6
Time (h)
Avibactam Plasma Concentration (µg/mL)
B
Young men Young women Elderly men Elderly women
55 50 45 40 35 30 25 20 15 10 5 0 0
2
4
6
8 10 12 14 16 18 20 22 24 Time (h)
Figure. Mean (SD) avibactam plasma concentrations over (A) the first 6 hours and (B) 24 hours.
warrant dose adjustment in clinical practice. Cmax was broadly comparable across cohorts but was slightly lower for elderly male subjects. Mean creatinine clearance (CrCL) values were numerically different across cohorts, with young subjects exhibiting higher values than elderly subjects (as expected). Because renal excretion is the main elimination pathway of avibactam,12,13 differences in CrCL affect renal clearance values; these values were somewhat lower in elderly men (6.93 L/h), and lower still in elderly women (4.51 L/h), than in young male and female subjects (9.23 and 8.62 L/h, respectively). This provides a plausible mechanistic explanation for the apparent age-related change in AUC, with mean
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AUC being comparable in young male subjects and in female and elderly male subjects, but greater in elderly female subjects. The reason for the lower renal excretion in elderly women than in elderly men does not seem to be related to differences in CrCL alone, but it is not anticipated to have a clinically significant impact on exposure to avibactam. In both elderly male and female subjects, plasma levels of avibactam were detectable for longer and the t½ was longer than in younger subjects, which may be partly due to the reduced renal function generally observed in elderly subjects. Furthermore, least squares mean Cmax was 12% lower (90% CI, 24% lower to 2% higher) and least squares mean AUC0-1 was 17% higher (90% CI, 5% to 31% higher) in the elderly cohort compared with the young cohort. Overall, these findings suggest a potential for somewhat higher exposure in the elderly. However, there was considerable overlap between the 4 cohorts in the range of values for AUC0-inf (lowest mean value 49.75 μg h/mL in young women; highest mean value 66.23 μg h/mL in elderly women) and Cmax (lowest mean value 26.45 μg/mL in elderly males and highest mean value 38.41 μg/mL in elderly females). In addition, based on the moderate nature of the difference in magnitude between groups in exposure, a dose adjustment is not warranted in the elderly. We showed that avibactam underwent predominantly renal excretion, with a mean of 91% and 86% of the dose recovered in urine within 24 hours of administration in the young male and female cohorts, respectively. Urinary excretion in the first 24 hours after dosing was lower in the elderly cohorts (68% in elderly men and 60% in elderly women), possibly reflecting age-related differences in renal function. Although these results confirm earlier findings that avibactam excretion is primarily via the renal route,12,13 it should be noted that in 8 patients, urinary recovery was 4100% (maximum recovery was 140% in 1 patient). These results may be due to inaccuracy in recording the volume of urinary sampling or the propagation of individual errors when deriving cumulative recovery data. In addition, avibactam was shown to be generally well tolerated in the healthy volunteers in this study. Overall, AEs were reported by 11 (33%) subjects who experienced a total of 20 events. Although more AEs were reported by female subjects (particularly in 1 elderly woman who reported 4 adverse events) than
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A. Tarral and H. Merdjan
Table II. Pharmacokinetic parameters. Unless otherwise stated, values are arithmetic mean (%CV). Pharmacokinetic parameter Cmax, mg/mL Tmax, h* T0–last, h* t1/2, h Plasma clearance, L/h Vss, L AUC0-t, μg h/mL AUC0–inf, μg h/mL Urinary excretion (% of dose in 24 hours) CLR over 0–24 hours, L/h†
Young Male Subjects: 18–45 y (n ¼ 9) 33.83 0.52 12.00 2.09 10.16 16.84 49.65 49.86 91.45
(12.52) (0.50–0.75) (11.98–24.08) (30.38) (12.10) (15.43) (12.57) (12.57) (41.63)
9.23 (67.56)
Young Female Subjects: 18–45 y (n ¼ 8) 36.86 0.50 12.00 1.71 10.34 15.20 49.59 49.75 85.91
(25.25) (0.50–0.75) (12.00–12.03) (5.22) (17.64) (24.12) (18.31) (18.28) (26.62)
8.62 (18.44)
Elderly Male Subjects: Z65 y (n ¼ 8) 26.45 0.50 24.03 3.17 9.82 24.29 52.29 52.40 67.89
(21.67) (0.50–1.00) (23.95–24.15) (20.65) (18.47) (24.15) (17.99) (17.90) (33.01)
6.93 (47.21)
Elderly Female Subjects: Z65 y (n ¼ 8) 38.41 0.50 24.03 2.43 7.98 16.72 65.90 66.23 59.73
(40.39) (0.50–0.53) (7.97–24.15) (19.29) (27.80) (26.48) (23.33) (22.60) (45.49)
4.51 (35.97)
CL ¼ plasma clearance; t1/2 ¼ terminal half-life; T0–last ¼ time of last quantifiable concentration; Vss ¼ apparent volume of distribution at steady state; CLR ¼ renal clearance. * Median (range). † %CV values for CLR were calculated using log-transformed data.
by male subjects, all AEs were of mild intensity and resolved by the end of the study. The most commonly reported AE was administration/venipuncture site bruising; all other AEs were isolated reports. Three subjects experienced AEs considered possibly related to the study drug: headache in 1 male subject; arthralgia, feeling jittery, feeling hot, and hyperhidrosis in 1 female subject; and dry mouth and dysgeusia in another female subject. The results of the present study confirm the results of a previous study evaluating the safety, tolerability, and pharmacokinetics of single, ascending doses of avibactam (50–2000 mg) in 70 healthy male subjects.12 Over the dose range, mean plasma clearance ranged from 10.4 to 13.8 L/h, volume of distribution from 19.5 to 24.3 L, and t½ from 1.5 to 2.7 hours. By way of comparison, in young male subjects in our study receiving avibactam 500 mg, mean plasma clearance was 10.16 L/h, volume of distribution was 16.8 L, and t½ was 2.09 hours; these findings were similar to the previous study. Avibactam pharmacokinetics were shown to be linear over the whole dose range (50–2000 mg), and avibactam was well tolerated in the previous study as well.
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The generalizability of the present study is limited due to the small sample size (33 subjects across 4 cohorts). Nevertheless, the small differences noted in AUC between the age cohorts in the present study are not sufficient to warrant dose adjustments in elderly subjects. However, as would be expected based on the predominantly renal excretion of avibactam, previous studies suggest that dose adjustments are required in subjects with renal impairment.16,17 In addition, the present study did not stratify patients according to race or ethnicity, and there was a disparity between groups in this regard (Table I). Studies to investigate the influence of race on the safety and pharmacokinetics of avibactam have recently been completed in Chinese and Japanese populations (NCT01920399 and NCT01291602, respectively). The choice of the 500-mg avibactam dose used in the present study was based on safety and tolerability data obtained in the single ascending dose study12 and is an appropriate dose of avibactam based on in vitro susceptibility testing, hollow fiber experiments, and preclinical data.18–21 In addition, avibactam 500 mg is the therapeutic dose being used in ongoing and recently completed Phase III clinical studies (NCT01726023, NCT01499290, NCT01500239,
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Clinical Therapeutics
Table III. Treatment-emergent adverse events (AEs) (no. [%]) regardless of perceived relationship to study drug (safety population).
AE Subjects with any AE Total no. of AEs observed Individual AEs observed Administration site bruising Venipuncture site bruising Headache Arthralgia Chest discomfort Cough Diarrhea Dry mouth Dysgeusia Fatigue Feeling hot Feeling jittery Hyperhidrosis Upper respiratory tract infection
Young Male Subjects: 18–45 y (n ¼ 9)
Young Female Subjects: 18–45 y (n ¼ 8)
Elderly Male Subjects: Z65 y Elderly Female Subjects (n ¼ 8) Z65 y (n ¼ 8)
1 (11.1) 1
3 (37.5) 7
2 (25.0) 2
5 (62.5) 10
0
1 (12.5)a
1 (12.5)
1 (12.5)b
0
1 (12.5)a
1 (12.5)
1 (12.5)b
1 (11.1)* 0 0 0 0 0 0 0 0 0 0 0
1 (12.5)a 0 1 (12.5)c 1 (12.5)c 1 (12.5)c 0 0 0 0 0 0 1 (12.5)
0 0 0 0 0 0 0 0 0 0 0 0
0 1 (12.5)d 0 0 1 (12.5) 1 (12.5)e* 1 (12.5)e* 1 (12.5) 1 (12.5)d* 1 (12.5)d* 1 (12.5)d* 0
Note: Letters “a” to “e” denote multiple AEs occurring in a single subject. * AEs considered possibly related to study medication. These were recorded in 1 young male subject and 2 elderly female subjects overall.
NCT01595438, NCT01599806, NCT01808092, and NCT01644643). Avibactam is currently being studied clinically in combination with ceftazidime and ceftaroline fosamil, and it may potentially be evaluated with other β-lactams, to determine whether it restores the activity of these antimicrobial agents against resistant Gramnegative bacterial pathogens. The results of a single ascending dose study in healthy male volunteers suggested that the pharmacokinetic parameters of avibactam are similar, whether given alone or in combination with ceftazidime.12 When tested against ESBL-producing Escherichia coli and K pneumoniae
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isolates, avibactam restored susceptibility to ceftazidime and several other cephalosporin antibiotics for all isolates tested.22
CONCLUSIONS Avibactam was generally well tolerated in the healthy young and elderly male and female cohorts in the present study. There were no notable differences in pharmacokinetic parameters between the male and female cohorts. The small differences in pharmacokinetic parameters between the young and elderly cohorts are not sufficient to warrant dose adjustments based on age beyond that necessary due to reduced renal function.
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A. Tarral and H. Merdjan
ACKNOWLEDGMENTS The authors thank Joy Lipka and Carole Sable (formerly of Novexel); Shwe Gyaw, Pepi Pencheva, and Rachel Garner (formerly of Parexel International); and Walter Heber (Parexel International) for their contributions to the study. Pepi Pencheva is currently at DP Clinical, Inc. This study was led by Novexel. Ceftazidimeavibactam is currently being developed by AstraZeneca and Forest-Cerexa, now a subsidiary of Actavis. Medical writing support was provided by Caroline Shapland, and editorial support was provided by Liz Anfield and Catherine Savage, all of Prime Medica Ltd, Knutsford, Cheshire funded by AstraZeneca. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.
CONFLICTS OF INTEREST A. Tarral and H. Merdjan were employees of Novexel SA at the time of conduct of the studies. The study sponsor was involved in the study design, collection, analysis, and interpretation of the data.
REFERENCES 1. Peleg AY, Hooper DC. Hospital-acquired infections due to Gram-negative bacteria. N Engl J Med. 2010;362:1804–1813. 2. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant Gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011;86:250–259. 3. Nordmann P, Nass T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis. 2011;17:1791–1798. 4. Stachyra T, et al. In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother. 2009;64:326–329. 5. Castanheira M, Sader HS, Farrell DJ, et al. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother. 2012;56:4779–4785. 6. Livermore DM, Mushtaq S, Warner M, et al. NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. J Antimicrob Chemother. 2008;62:1053–1056.
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7. Miossec C, Claudon M, Levasseur P, Black MT. The β-lactamase inhibitor avibactam (NXL104) does not induce ampC β-lactamase in Enterobacter cloacae. Infect Drug Resist. 2013;6:235–240. 8. Stachyra T, et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010; 54:5132–5138. 9. Lucasti C, Popescu I, Ramesh M, et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68:1183–1192. 10. Vazquez JA, et al. Efficacy and safety of ceftazidimeavibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28:1921–1931. 11. Livermore DM, et al. Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemaseproducing Enterobacteriaceae. Antimicrob Agents Chemother. 2011;55:390–394. 12. Merdjan, H. et al. Safety, single dose pharmacokinetics, and pharmacodynamics of beta-lactamase inhibitor NXL104 in healthy young male adults. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois (2007). Abstract A-809. 13. Vishwanathan K, et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential. Drug Metab Dispos. 2014;42:932–942. 14. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57:6–14. 15. Whitley H, Lindsey W. Sex-based differences in drug activity. Am Fam Physician. 2009;80:1254–1258. 16. Felices M, Gualano V, Tarral A, et al. Combined population pharmacokinetic analysis of four phase 1 studies with NXL104. 20th European Congress of Clinical Microbiology and Infectious Diseases Vienna, Austria (2010). Abstract P1599. 17. Merdjan H, Tarral A, Haazen W, et al. Pharmacokinetics and tolerability of NXL104 in normal subjects and patients with varying degrees of renal insufficiency. (Abstract P1598). Clin Microbiol Infect. 2010;16:S465. 18. Levasseur, P. et al. NXL104, a novel β-lactamase inhibitor, restores the bactericidal activity of ceftazidime against ESBL and AmpC producing strains of Enterobacteriaceae. 46th International Conference on Antimicrobial Agents and Chemotherapy San Francisco, California (2006). Abstract F127.
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Clinical Therapeutics 19. Coleman K, et al. Activities of ceftazidime and avibactam against β-lactamase-producing Enterobacteriaceae in a hollow-fiber pharmacodynamic model. Antimicrob Agents Chemother. 2014;58:3366–3372. 20. Endimiani A, Choudhary Y, Bonomo RA. In vitro activity of NXL104 in combination with beta-lactams against Klebsiella pneumoniae isolates producing KPC carbapenemases. Antimicrob Agents Chemother. 2009;53: 3599–3601. 21. Endimiani A, Hujer KM, Hujer AM, et al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011;55:82–85. 22. Lagacé-Wiens PR, et al. Activity of NXL104 in combination with β-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing Class A extended-spectrum beta-lactamases and Class C beta-lactamases. Antimicrob Agents Chemother. 2011;55:2434–2437.
Address correspondence to: Antoine Tarral, MD, DNDi Drugs for Neglected Diseases Initiative, 15 chemin Louis-Dunant, 1202 Geneva, Switzerland. E-mail: [email protected]
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