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- Title
A Mechanistic In Vivo/Ex Vivo Pharmacokinetic‐Pharmacodynamic Model of Tenofovir for HIV Prevention.
- Authors
Jayachandran, Priya; Garcia-Cremades, Maria; Vučićević, Katarina; Bumpus, Namandjé N.; Anton, Peter; Hendrix, Craig; Savić, Radojka
- Abstract
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.
- Subjects
MONONUCLEAR leukocytes; HIV prevention; GLYCOPYRROLATE; TENOFOVIR; PRE-exposure prophylaxis; HIV
- Publication
CPT: Pharmacometrics & Systems Pharmacology, 2021, Vol 10, Issue 3, p179
- ISSN
2163-8306
- Publication type
Article
- DOI
10.1002/psp4.12583