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A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention

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2021
A_Mechanisti_In_pub_2021.pdf (793.7Kb)
Authors
Jayachandran, Priya
Garcia-Cremades, Maria
Vučićević, Katarina
Bumpus, Namandjé
Anton, Peter
Hendrix, Craig
Savić, Radojka
Article (Published version)
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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 appa...rent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.

Source:
CPT: Pharmacometrics and Systems Pharmacology, 2021
Publisher:
  • American Society for Clinical Pharmacology and Therapeutics
Projects:
  • Pre- Clinical/Clinical HIV Topical Microbicide Program (U19 AI AI060614)
  • Microbicide Trials Network Laboratory Center (UM1 AI106707)
  • Bill and Melinda Gates Foundation (Contract ID OPP1099837)
  • Johns Hopkins University Center for AIDS Research (P30 AI042855)
  • P.J. was supported by grant T32 GM007546 from the National Institute of General Medical Sciences (NIGMS).

DOI: 10.1002/psp4.12583

ISSN: 2163-8306

Scopus: 2-s2.0-85100593175
[ Google Scholar ]
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3785
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  • Radovi istraživača / Researchers’ publications
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Pharmacy

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