title: Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials.
abstract: Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) μg · h/ml and 138 (23%) μg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2α), t1/2β, and t1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA CRubino@ICPD.com.
authors.forename: C M
authors.initials: CM
authors.lastname: Rubino
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Bhavnani
authors.affiliation: The Medicines Company, Parsippany, New Jersey, USA.
authors.forename: G
authors.initials: G
authors.lastname: Moeck
authors.affiliation: The Medicines Company, Parsippany, New Jersey, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Bellibas
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D006020:Glycopeptides / Q000493:pharmacokinetics*; D006801:Humans; D000077427:Lipoglycopeptides; D008875:Middle Aged; D009010:Monte Carlo Method; D055815:Young Adult; D014640:Vancomycin / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D000077427:Lipoglycopeptides; C100708:oritavancin; D014640:Vancomycin
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