Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection-Reference-Cited by-同舟云学术

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

Published:2018-01 Issue:1 Volume:62 Page:
ISSN:0066-4804
Container-title:Antimicrobial Agents and Chemotherapy
language:en
Short-container-title:Antimicrob Agents Chemother

Author:

Xiao Peng¹,Gumber Sanjeev²,Marzinke Mark A.³⁴,Date Abhijit A.⁵⁶,Hoang Thuy⁵⁷,Hanes Justin⁵⁸,Ensign Laura M.⁵⁶⁹⁷⁸,Wang Lin¹⁰,Rohan Lisa¹⁰,Fuchs Edward J.³,Hendrix Craig³⁷,Villinger Francois¹

Affiliation:

1. New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA

2. Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

5. Center for Nanomedicine, Johns Hopkins University, Baltimore, Maryland, USA

6. Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland, USA

7. Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA

8. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA

9. Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA

10. Magee's Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Abstract

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 in ex vivo challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | NIH Office of the Director

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Link

https://journals.asm.org/doi/pdf/10.1128/AAC.01644-17

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