Pharmacokinetics of ABT-773, a new semi-synthetic ketolide in neutropenic lung-infected mice: a population approach

Abstract

ABT-773 is an investigational ketolide antimicrobial agent with an in-vitro bactericidal activity against macrolide-susceptible and -resistant Streptococcus pneumoniae. The pharmacokinetics of this drug candidate were evaluated in lung-infected (108 CFU mL−1 starting inoculum) mice following a single dose (25, 50, 100 or 200 mg kg−1) oral administration as a solution in 10 % of 95% ethanol and 90% of 0.1 M pH 6.5 phosphate buffer solution. Serum ABT-773 concentrations were measured using a validated HPLC assay with fluorescence detection (excitation at 324 nm and emission at 364 nm). Population pharmacokinetic analysis was performed using the NONMEM computer program. Results from data analysis showed non-linear pharmacokinetics of ABT-773, noted by the increases in half-life (3.1 to 27.2 h) and AUC/dose (23.7 to 149 mg h−1 L−1 mg−1), with doses from 25 to 200 mg kg−1. A non-linear one-compartment model with parallel capacity-limited and linear first-order elimination best described the pharmacokinetics of ABT-773 in the mouse. The total volume of distribution was 0.316 L. The clearance for the linear first-order elimination was 0.0027 L h−1. The Vm and Km were 0.0385 L h−1 and 0.141 mg L−1, respectively, for the capacity-limited elimination.