title: Population pharmacokinetics of bedaquiline (TMC207), a novel antituberculosis drug.
abstract: Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.
authors: Model Answers Pty Ltd., Brisbane, Queensland, Australia sarah.mcleay@gmail.com.
authors: Sarah C
authors: SC
authors: McLeay
authors: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors: Peter
authors: P
authors: Vis
authors: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors: Rolf P G
authors: RP
authors: van Heeswijk
authors: Model Answers Pty Ltd., Brisbane, Queensland, Australia.
authors: Bruce
authors: B
authors: Green
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D064687:Diarylquinolines / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline