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Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

ABSTRACT: Plazomicin is an aminoglycoside with activity against multidrug-resistant Enterobacteriaceae Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24?h, with dose adjustments being made for renal impairment and a body weight (BW) of ?125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3). A three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the ?-, ?-, and ?-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08?liters/h, respectively. Starting dose adjustments for CLCR are sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.

SUBMITTER: Trang M

PROVIDER: S-EPMC6496156 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

Trang Michael M Seroogy Julie D JD Van Wart Scott A SA Bhavnani Sujata M SM Kim Aryun A Gibbons Jacqueline A JA Ambrose Paul G PG Rubino Christopher M CM

Antimicrobial agents and chemotherapy 20190327 4

Plazomicin is an aminoglycoside with activity against multidrug-resistant <i>Enterobacteriaceae</i> Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are ...[more]

PMID: 30670433

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Project description:Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Dataset Information

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

Publications

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

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