Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model.

Abstract

Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice. Mice received 200mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF+EVG solution) or as drug loaded NP (TAF+EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin. SubQ administration of TAF+EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0-72h) of TFV and EVG was 14.1±2.0, 7.2±1.8μg×hr./mL from drugs in solution (free) and the AUC(0-14day) for the same drugs was 23.1±4.4, 39.7±6.7μg×hr./mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2h, 5.1days and for EVG 10.8h, 3.3days, respectively. This study documents that a TAF+EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis.