title: Population pharmacokinetics of tenofovir and tenofovir-diphosphate in healthy women.
abstract: The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir-diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN-001 clinical trial, an open label 3-way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2-compartment, first-order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV-DP by first-order uptake with first-order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (Vc ) with estimates as follows: absorption rate constant (Ka) 9.79 h(-1) , absorption lag time 0.5 hours, Vc 385.71-2.16*(73-WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*Vc ). TFV-DP's half-life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN-001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV-DP when compared to healthy participant data from another clinical trial.
authors.affiliation: Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Atlanta, GA, USA.
authors.forename: Rebecca N
authors.initials: RN
authors.lastname: Burns
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Ayyappa
authors.initials: A
authors.lastname: Chaturvedula
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D018592:Cross-Over Studies; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D008875:Middle Aged; D010755:Organophosphates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068698:Tenofovir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014621:Vagina / Q000187:drug effects; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000493:pharmacokinetics; D014930:Women; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D010755:Organophosphates; D014622:Vaginal Creams, Foams, and Jellies; C583447:tenofovir diphosphate; D000068698:Tenofovir; D000225:Adenine
keywords: adherence; population pharmacokinetics; tenofovir; tenofovir-diphosphate