Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination

A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission

Subhra Mandal, Guobin Kang, Pavan Kumar Prathipati, You Zhou, Wenjin Fan, Qingsheng Li, Christopher J. Destache

Research output: Contribution to journalArticle

Abstract

Daily oral antiretroviral (ARV) drugs for pre-exposure prophylaxis (PrEP) has proven efficacy for diverse groups of high-risk individuals. However, daily dosing regimen has augmented non-adherence. These experiments comparatively investigated the long-acting (LA) PrEP potency of subcutaneous (SubQ) administrated tenofovir alafenamide (TAF) and emtricitabine (FTC) loaded nanoparticles (NPs) to solution in humanized (hu) mice. TAF + FTC NPs and TAF + FTC solution (each drug at 200 mg/kg) were administered to hu-CD34-NSG mice (n = 3/time point) for plasma and tissue pharmacokinetic parameter estimation using LC-MS/MS. NP enhanced tissue ARV assimilation compared to plasma. The same dose was administered for PrEP efficacy in HIV-1 challenged hu-BLT mice (n = 5/group). The hu-BLT mice were vaginally challenged with a transmission-founder (T/F) virus at 5 × 105 TCID50 inoculation, on day 4, 7 and 14 post-SubQ treatments (PT) and were compared to infected-untreated-control hu-BLT mice. By 21 days PT, 100% TAF + FTC solution-treated and control-untreated mice were infected. However, TAF + FTC NPs resulted in significant (p =.0002) protection from HIV-1 (day 4: 80%, day 7 and 14: 60%, respectively) compared to control mice. This proof-of-concept study demonstrated detectable TAF/FTC vaginal levels among TAF + FTC NP-treated hu-BLT mice correlating with prolonged PrEP efficacy, thus establishing long-acting TAF + FTC NPs as a potential PrEP modality.

Original languageEnglish (US)
Pages (from-to)216-225
Number of pages10
JournalJournal of Controlled Release
Volume294
DOIs
StatePublished - Jan 28 2019

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Drug Combinations
HIV-1
Nanoparticles
GS-7340
Pre-Exposure Prophylaxis
Emtricitabine
Pharmaceutical Preparations
Pharmacokinetics
Viruses

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination : A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission. / Mandal, Subhra; Kang, Guobin; Prathipati, Pavan Kumar; Zhou, You; Fan, Wenjin; Li, Qingsheng; Destache, Christopher J.

In: Journal of Controlled Release, Vol. 294, 28.01.2019, p. 216-225.

Research output: Contribution to journalArticle

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abstract = "Daily oral antiretroviral (ARV) drugs for pre-exposure prophylaxis (PrEP) has proven efficacy for diverse groups of high-risk individuals. However, daily dosing regimen has augmented non-adherence. These experiments comparatively investigated the long-acting (LA) PrEP potency of subcutaneous (SubQ) administrated tenofovir alafenamide (TAF) and emtricitabine (FTC) loaded nanoparticles (NPs) to solution in humanized (hu) mice. TAF + FTC NPs and TAF + FTC solution (each drug at 200 mg/kg) were administered to hu-CD34-NSG mice (n = 3/time point) for plasma and tissue pharmacokinetic parameter estimation using LC-MS/MS. NP enhanced tissue ARV assimilation compared to plasma. The same dose was administered for PrEP efficacy in HIV-1 challenged hu-BLT mice (n = 5/group). The hu-BLT mice were vaginally challenged with a transmission-founder (T/F) virus at 5 × 105 TCID50 inoculation, on day 4, 7 and 14 post-SubQ treatments (PT) and were compared to infected-untreated-control hu-BLT mice. By 21 days PT, 100{\%} TAF + FTC solution-treated and control-untreated mice were infected. However, TAF + FTC NPs resulted in significant (p =.0002) protection from HIV-1 (day 4: 80{\%}, day 7 and 14: 60{\%}, respectively) compared to control mice. This proof-of-concept study demonstrated detectable TAF/FTC vaginal levels among TAF + FTC NP-treated hu-BLT mice correlating with prolonged PrEP efficacy, thus establishing long-acting TAF + FTC NPs as a potential PrEP modality.",
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