Population pharmacokinetic analyses for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections

Abstract

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.).

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Figures

FIG 1

Semilog scatterplots of plasma drug concentrations versus time since the start of the last dose, stratified by study visit and separated by dose.

FIG 2

Covariate screening plots. Abbreviations: AGEY, age in years; WTKG, weight in kilograms; HTCM, height in centimeters; ALB, serum albumin concentration in grams per deciliter; BSA, body surface area in square meters; BMI, body mass index in kilograms per square meter; CLCR, creatinine clearance in milliliters per minute per 1.73 m2; CLtu, total clearance of free drug; Vcu, volume of the central compartment for free drug; Vssu, steady-state volume of distribution of free drug.

FIG 3

Goodness-of-fit plots for the final population PK model. Obs., observed. r2, overall coefficient of determination.

FIG 4

Precision of the individual clearance estimates from the final population PK model. The vertical band represents the median value (9.15%).