title: Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin.
abstract: Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one-compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug-resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure-response analyses.
authors.affiliation: Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: E M
authors.initials: EM
authors.lastname: Svensson
authors.affiliation: Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: A-G
authors.initials: AG
authors.lastname: Dosne
authors.affiliation: Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: M O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000328:Adult; D000418:Albumins / Q000378:metabolism; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D001835:Body Weight / Q000187:drug effects; D060085:Coinfection; D064687:Diarylquinolines / Q000493:pharmacokinetics*; D004309:Double Bind Interaction; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000208:ethnology; D055815:Young Adult
chemical_list: D000418:Albumins; D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline