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.)

Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing

“…PK exposure and secondary PK parameter estimates were calculated for each patient by simulating a concentration–time profile using the final population PK model. Secondary PK parameters were obtained by applying non-compartmental analysis methods to the simulated profiles 14 . For all other studies, PK parameters C max , T max , AUC 0–12 , AUC 0–24 and AUC 0–∞ were calculated using SAS ® Version 9.1.3 or higher (SAS Institute, Cary, NC, USA).…”

The good, the bad and the tasty: The many roles of mushrooms

“…Research is still ongoing to develop novel pleuromutilin derivatives that could be employed as systemic antibiotics in human medicine (Ling et al., 2014, Zhang et al., 2015). One very promising compound is lefamulin, a pleuromutilin derivative developed by Nabriva Therapeutics that is soon to be entering phase III clinical trials for the treatment of moderate to severe CAPB (community-acquired bacterial pneumonia) (Prince et al., 2013, Rubino et al., 2015, Waites et al., 2016). Fig.…”

In Vitro Activity of Lefamulin Tested against Streptococcus pneumoniae with Defined Serotypes, Including Multidrug-Resistant Isolates Causing Lower Respiratory Tract Infections in the United States

“…Lefamulin is the first pleuromutilin in development for intravenous and oral administration in humans (6), and it is currently in late-stage clinical development for the treatment of CABP and acute bacterial skin and skin structure infections (11)(12)(13). Lefamulin exhibits potent antibacterial activity against the most important respiratory and skin pathogens, including Streptococcus spp.…”