A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention
2021
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Authors
Jayachandran, PriyaGarcia-Cremades, Maria
Vučićević, Katarina
Bumpus, Namandjé
Anton, Peter
Hendrix, Craig
Savić, Radojka
Article (Published version)
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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, 10, 179-187Publisher:
- American Society for Clinical Pharmacology and Therapeutics
Funding / 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
WoS: 000615319000001
Scopus: 2-s2.0-85100593175
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PharmacyTY - JOUR AU - Jayachandran, Priya AU - Garcia-Cremades, Maria AU - Vučićević, Katarina AU - Bumpus, Namandjé AU - Anton, Peter AU - Hendrix, Craig AU - Savić, Radojka PY - 2021 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3785 AB - 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. PB - American Society for Clinical Pharmacology and Therapeutics T2 - CPT: Pharmacometrics and Systems Pharmacology T1 - A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention VL - 10 SP - 179 EP - 187 DO - 10.1002/psp4.12583 ER -
@article{ author = "Jayachandran, Priya and Garcia-Cremades, Maria and Vučićević, Katarina and Bumpus, Namandjé and Anton, Peter and Hendrix, Craig and Savić, Radojka", year = "2021", 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.", publisher = "American Society for Clinical Pharmacology and Therapeutics", journal = "CPT: Pharmacometrics and Systems Pharmacology", title = "A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention", volume = "10", pages = "179-187", doi = "10.1002/psp4.12583" }
Jayachandran, P., Garcia-Cremades, M., Vučićević, K., Bumpus, N., Anton, P., Hendrix, C.,& Savić, R.. (2021). A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention. in CPT: Pharmacometrics and Systems Pharmacology American Society for Clinical Pharmacology and Therapeutics., 10, 179-187. https://doi.org/10.1002/psp4.12583
Jayachandran P, Garcia-Cremades M, Vučićević K, Bumpus N, Anton P, Hendrix C, Savić R. A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention. in CPT: Pharmacometrics and Systems Pharmacology. 2021;10:179-187. doi:10.1002/psp4.12583 .
Jayachandran, Priya, Garcia-Cremades, Maria, Vučićević, Katarina, Bumpus, Namandjé, Anton, Peter, Hendrix, Craig, Savić, Radojka, "A Mechanistic In Vivo/Ex Vivo Pharmacokinetic-Pharmacodynamic Model of Tenofovir for HIV Prevention" in CPT: Pharmacometrics and Systems Pharmacology, 10 (2021):179-187, https://doi.org/10.1002/psp4.12583 . .