替诺福韦和替诺福韦艾拉酚胺用于包皮组织中HIV-1暴露前预防的临床前评估

Pre-Clinical Evaluation of Tenofovir and Tenofovir Alafenamide for HIV-1 Pre-Exposure Prophylaxis in Foreskin Tissue.

作者信息

Else Laura, Penchala Sujan D, Pillay Azure-Dee, Seiphetlo Thabiso B, Lebina Limakatso, Callebaut Christian, Minhas Suks, Morley Roland, Rashid Tina, Martinson Neil, Fox Julie, Khoo Saye, Herrera Carolina

机构信息

Bioanalytical Facility, Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK.

Division of Immunology, University of Cape Town, Cape Town 7935, South Africa.

出版信息

Pharmaceutics. 2022 Jun 16;14(6):1285. doi: 10.3390/pharmaceutics14061285.

DOI:10.3390/pharmaceutics14061285

PMID:35745857

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9227286/

Abstract

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

Inner and outer foreskin explants were exposed to serial dilutions of TFV or TAF prior to addition of HIV-1 at a high (HVT) or a low viral titer (LVT). Infection was assessed by measurement of p24 in foreskin culture supernatants. TFV, TAF and TFV-diphosphate (TFV-DP) concentrations were measured in tissues, culture supernatants and dosing and washing solutions.

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

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.

摘要

背景

HIV-1暴露前预防（PrEP）主要侧重于接受性性行为中的保护效果，而对于插入性性行为的给药要求研究有限。我们在临床前评估了替诺福韦（TFV）和替诺福韦艾拉酚胺（TAF）在包皮组织中的体外药代动力学-药效学（PK-PD）特征。

方法

在添加高病毒滴度（HVT）或低病毒滴度（LVT）的HIV-1之前，将包皮内、外植体暴露于TFV或TAF的系列稀释液中。通过测量包皮培养上清液中的p24来评估感染情况。在组织、培养上清液以及给药和洗涤溶液中测量TFV、TAF和二磷酸替诺福韦（TFV-DP）的浓度。

结果

获得了两种药物的剂量反应曲线，观察到对LVT的效力更强。在针对HVT攻击时，1 mg/mL的TFV与15 µg/mL的TAF之间定义了模拟口服给药的抑制等效性。用TAF进行体外给药后，包皮外植体中TFV-DP的浓度比用TFV给药时高约6倍。在HVT后，观察到TFV或TFV-DP的外植体水平与p24浓度之间存在统计学上显著的负线性相关性。