title: Population Pharmacokinetics of Tenofovir in HIV-1-Uninfected Members of Serodiscordant Couples and Effect of Dose Reporting Methods.
abstract: Antiretroviral preexposure prophylaxis (PrEP) with once-daily dosing of tenofovir and tenofovir-emtricitabine was shown to be effective for preventing HIV-1 infection in individuals who had HIV-1-seropositive partners (the Partners PrEP Study). We developed a population pharmacokinetic model for tenofovir and investigated the impacts of different dose reporting methods. Dosing information was collected as patient-reported dosing information (PRDI) from 404 subjects (corresponding to 1,280 drug concentration records) from the main trial and electronic monitoring-based adherence data collected from 211 subjects (corresponding to 327 drug concentration records) in an ancillary adherence study. Model development was conducted with NONMEM (7.2), using PRDI with a steady-state assumption or using PRDI replaced with electronic monitoring records where available. A two-compartment model with first-order absorption was the best model in both modeling approaches, with the need for an absorption lag time when electronic monitoring-based dosing records were included in the analysis. Age, body weight, and creatinine clearance were significant covariates on clearance, but only creatinine clearance was retained in the final models per stepwise selection. Sex was not a significant covariate on clearance. Tenofovir population pharmacokinetic parameter estimates and the precisions of the parameters from the two final models were comparable with the point estimates of the parameters, differing from 0% to 35%, and bootstrap confidence intervals widely overlapped. These findings indicate that PRDI was sufficient for population pharmacokinetic model development in this study, with a high level of adherence per multiple measures.
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Goti
authors.affiliation: Pharmaceutical Sciences, Mercer University, Atlanta, Georgia, USA ayyappa.chaturvedula@unthsc.edu.
authors.forename: Ayyappa
authors.initials: A
authors.lastname: Chaturvedula
authors.affiliation: Center for Global Health, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Haberer
authors.affiliation: Quantitative Sciences, Trevena Inc., King of Prussia, Pennsylvania, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fossler
authors.affiliation: Nuventra, Durham, North Carolina, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sale
authors.affiliation: Center for Global Health, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bangsberg
authors.affiliation: Departments of Global Health, Medicine, and Epidemiology, University of Washington, Seattle, Washington, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Baeten
authors.affiliation: Departments of Global Health, Medicine, and Epidemiology, University of Washington, Seattle, Washington, USA.
authors.forename: Connie L
authors.initials: CL
authors.lastname: Celum
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D057286:Electronic Health Records; D000068679:Emtricitabine / Q000097:blood / Q000493:pharmacokinetics*; D005191:Family Characteristics; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D055118:Medication Adherence; D015233:Models, Statistical; D008991:Monitoring, Physiologic; D065129:Pre-Exposure Prophylaxis / Q000379:methods; D012747:Sexual Partners; D000068698:Tenofovir / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir; D003404:Creatinine; D000068679:Emtricitabine