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A multi-compartment pharmacokinetic model for the administration of tenofovir as an oral tablet and rectal enema in rhesus macaques
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2020 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesisAlternative title
En farmakokinetisk populationsmodell för administrering av tenofovir som oral tablett och lavemang i rhesusapor (Swedish)
Abstract [en]

Objectives: Tenofovir disoproxil fumarate (TDF) as oral pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition via sexual transmission but is associated with issues of adherence. Topical microbicides offer the possibility of improved PrEP adherence. Our goal is to characterize the pharmacokinetics (PK) of tenofovir (TFV) and tenofovir-diphospate (TFVdp) in plasma and rectal tissue matrices for oral TDF and rectal TFV enema formulations.

Methods: Using a multi-compartment population PK (popPK) model, we characterized the PK profiles for two formulations: oral tablet (TDF dose: high = 22 mg/kg, low = 5 mg/kg) and rectal enema (hypo-osmolar (HOsm) and iso-osmolar (IOsm) TFV dose: high = 158 mg, low = 53 mg) in rheus macaques. A 1-comparmtent popPK model described the plasma TFV profiles and distinct biophase distribution compartments linked plasma TFV concentrations to rectal tissue TFV and TFVdp concentrations. NONMEM 7.4.2 was used for model building.

Results: The plasma PK parameters (with standard error) were CL/F (34.5(7) L/h ), Vc/F (521 (9) L), ka (oral = 8.48(2), rectal = 0.864(6) hr-1),  F for each enema (low HOsm = 0.24(5), high HOsm = 0.34(8), low IOsm = 0.36(7), high IOsm = 0.10(17)). The effect compartment parameters were: rate (TFV: oral  = 0.0961(24), rectal = 443(13)  hr-1, TFVdp: oral = 0.0343(6), rectal = 0.87(2) hr-1) and ratio (TFV: oral = 0.182(20), rectal = 7.78(12) [(ng/mg)/(ng/mL], TFVdp: oral = 14.1(1), rectal = 84.2(5) [(fmol/mg)/(ng/mL)]).

Conclusion: Using this popPK model we have characterized the PK of oral tablet and rectal enema formulations for tenofovir. The high HOsm formulation had the highest drug concentrations in rectal tissue with plasma TFV concentrations comparable to low dose TDF.

Place, publisher, year, edition, pages
2020. , p. 29
Keywords [en]
PrEP, HIV, Tenofovir, Microbicdes, Modeling
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-405539OAI: oai:DiVA.org:uu-405539DiVA, id: diva2:1404150
External cooperation
Savic Lab, University of California San Francisco
Subject / course
Pharmacokinetics
Educational program
Master of Science Programme in Pharmacy
Supervisors
Examiners
Available from: 2020-03-02 Created: 2020-02-28 Last updated: 2020-03-02Bibliographically approved

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