Open AccessA Mechanistic In Vivo / Ex Vivo Pharmacokinetic‐Pharmacodynamic Model of Tenofovir for HIV Prevention
Author(s) -
Jayachandran Priya,
Garcia-Cremades Maria,
Vučićević Katarina,
Bumpus Namandjé N.,
Anton Peter,
Hendrix Craig,
Savić Radojka
Publication year - 2021
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12583
Subject(s) - ex vivo , pharmacokinetics , nonmem , peripheral blood mononuclear cell , pharmacodynamics , in vivo , pharmacology , population , reverse transcriptase inhibitor , medicine , immunology , human immunodeficiency virus (hiv) , biology , viral load , in vitro , antiretroviral therapy , biochemistry , microbiology and biotechnology , environmental health
Defining tissue and plasma‐specific prophylactic drug concentrations is central to pre‐exposure prophylaxis product development for sexual transmission of HIV‐1. Pharmacokinetic (PK) data from study RMP‐02/MTN‐006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV‐1 seronegative adults was used to construct a multicompartment plasma‐rectal tissue population PK model for TFV and tenofovir‐diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV‐1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.