A. Chaturvedula1, C. Celum3, J Baeten3, D Donnell3,4, D Bangsberg5, J. Haberer5, A Mujugira3, C. Hendrix2
(1)Center for Pharmacometrics, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA, USA. (2)Drug Development Unit, Johns Hopkins School of Medicine, Baltimore, MD, USA.(3) University of Washington, Seattle, WA, USA ( 4) Fred Hutchinson Cancer Research Center, Seattle, WA, USA. (5) Massachusetts General Hospital, Boston, MA, USA
Objectives: The study was performed to investigate gender differences in the pharmacokinetics of Tenofovir from the Partners pre-exposure prophylaxis (PrEP) study, a double-blind, placebo-controlled, randomized trial of tenofovir disoproxil fumarate (TDF) and emitricitabine (FTC)/TDF PrEP among 4747 HIV uninfected members of heterosexual HIV serodiscordant couples from Kenya and Uganda.
Methods: A population pharmacokinetic model for Tenofovir was developed from sparse samples (1 sample per occasion, multiple occasions) collected from 1154 observation records from 268 individuals sampled at random from the active drug arms of the study using a non-linear mixed effects model. The data was supplemented with another study MTN-001 where 6 samples were collected after oral administration. Measures below the limit of detection (BQL) were included in the modeling and M3 method was used for handling BQL.
Results: Tenofovir pharmacokinetics was well described by a two compartment open model. Typical population estimates of first order absorption rate constant (Ka), apparent central distribution volume (Vc/F), peripheral distribution volume (Vp/F), intercompartmental clearance (Q/F) and plasma clearance (CL/F) were 0.493/h, 81.7 L, 3790 L, 143 L/h and 50.5 L/h respectively. Between-subject-variability (CV) on Ka, Vc/F,Vp/F , Q/F and CL/F was estimated as 26%,74%,115%,38% and 32% , respectively. We estimated Ka as a separate parameter opposed to the previous attempts that assumed Ka equals the distribution constant. It could be driven by the availability of blood samples in the absorption phase from the MTN-001 study.
Conclusions: We utilized the non-linear mixed effect model to estimate the individual pharmacokinetic parameters from sparsely sampled population. Data pooling approach helped us to estimate fixed and random effect parameters for the population. No major differences were observed in the pharmacokinetic parameters between male and female.
Reference: PAGE 21 (2012) Abstr 2305 [www.page-meeting.org/?abstract=2305]
Poster: Infection