Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.
HIV-1
foreskin
pre-exposure prophylaxis
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
16 Jun 2022
16 Jun 2022
Historique:
received:
03
05
2022
revised:
30
05
2022
accepted:
12
06
2022
entrez:
24
6
2022
pubmed:
25
6
2022
medline:
25
6
2022
Statut:
epublish
Résumé
HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic-pharmacodynamic (PK-PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue. Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1 Dose-response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV-DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV-DP and p24 concentrations following HVT. Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding.
Sections du résumé
BACKGROUND
BACKGROUND
HIV-1 pre-exposure prophylaxis (PrEP) has focused predominantly on protective efficacy in receptive sex, with limited research on the dosing requirements for insertive sex. We pre-clinically assessed the ex vivo pharmacokinetic-pharmacodynamic (PK-PD) profile of tenofovir (TFV) and tenofovir alafenamide (TAF) in foreskin tissue.
METHODS
METHODS
Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1
RESULTS
RESULTS
Dose-response curves were obtained for both drugs, with greater potency observed against LVT. Inhibitory equivalency mimicking oral dosing was defined between 1 mg/mL of TFV and 15 µg/mL of TAF against HVT challenge. Concentrations of TFV-DP in foreskin explants were approximately six-fold higher after ex vivo dosing with TAF than with TFV. Statistically significant negative linear correlations were observed between explant levels of TFV or TFV-DP and p24 concentrations following HVT.
CONCLUSIONS
CONCLUSIONS
Pre-clinical evaluation of TAF in foreskin explants revealed greater potency than TFV against penile HIV transmission. Clinical evaluation is underway to support this finding.
Identifiants
pubmed: 35745857
pii: pharmaceutics14061285
doi: 10.3390/pharmaceutics14061285
pmc: PMC9227286
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : European & Developing Countries Clinical Trials Partnership
ID : RIA2016MC - 1616 - CHAPS
Organisme : Gilead Sciences (United Kingdom)
ID : CO-UK-120-5494
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