Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection

Antimicrobial Agents and Chemotherapy
Peng XiaoFrancois Villinger

Abstract

Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively (P < 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection...Continue Reading

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Citations

Sep 11, 2018·Clinical Pharmacology and Therapeutics·Craig W Hendrix
Apr 3, 2019·PloS One·Maria Carmina PauFrancesco Michelangelo Turrini
Aug 14, 2019·Journal of Pharmaceutical Sciences·David H McAdamsManjari Quintanar-Solares
Jan 30, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kevin E LindsayPhilip J Santangelo
May 18, 2021·Advanced Therapeutics·Fernanda P Pons-FaudoaAlessandro Grattoni

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