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

Abstract

Purpose 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. Methods Mice received 200 mg/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. Results 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±1.8 μg×hr/mL from drugs in solution (free) and the AUC(0–14day) for the same drugs was 23.1±4.4, 39.7±6.7 μg×hr/mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. Conclusion 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.

Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study

“…The presence of substantially elevated IR fluorescence until the end of study (14 days post-injection) at the injection site and within clearance organs (liver and kidney) indicates at the injection site cARV NPs could act as a "cARV NP depo" inducing sustained NP release. The above observation follows the previous PK studies, reporting high cARVs concentration at the injection site and clearance organs at the terminal time-point (Prathipati et al, 2017).…”

“…Previous PK studies suggested that subQ injected cARV NP leads to ARVs target tissue-level significantly above the IC 90 (Mandal et al, 2017a(Mandal et al, , 2017bPrathipati et al, 2017) for all three studied ARVs. Compared to single cARV PK studies (Mandal et al, 2017a(Mandal et al, , 2017bPrathipati et al, 2017), multiple dosage of cARV NPs illustrated even higher tissue ARV levels at 22 week (2 weeks post-terminal dose, Table 2). Further, sustained non-detectable pVL (Fig.…”

A potential long-acting bictegravir loaded nano-drug delivery system for HIV-1 infection: A proof-of-concept study

“…BIC loaded NPs (BIC NPs) were formulated using previously reported oil-in-water (o-w) emulsion method with some modifications (Destache et al, 2016;Mandal et al, 2017c;Prathipati et al, 2017). Briefly, the 5 mL DCM (organic phase) containing PLGA, PF-127 (stabilizer) and BIC at 10:10:2 (w:w:w), respectively, was added dropwise to 20 mL of 1% PVA solution (aqueous phase), under high speed continuous stirring condition.…”

“…Various longacting injectable small molecule ARV agents are already in clinical trials (Spreen et al, 2013). Our research goal is to introduce long-action to conventional ARVs by fabricating single or multiple ARV (combination ARVs, cARVs) in polymeric nanoformulations as a long-acting parenteral drug delivery system for HIV treatment and prevention (Mandal et al, 2017b(Mandal et al, , 2017cPrathipati et al, 2017;Shibata et al, 2013). Our long-acting FTC NPs (Mandal et al, 2017a), TAF+FTC NPs as well as TAF+elvitegravir (EVG) NPs were efficacious as prevention regimens (Mandal et al, 2017b(Mandal et al, , 2017cPrathipati et al, 2017;Shibata et al, 2013), and TAF +FTC+EVG NPs demonstrated efficacy as chronic HIV treatment (Mandal et al, 2018) in humanized mice.…”

Reverse Transcriptase Inhibitors Nanosystems Designed for Drug Stability and Controlled Delivery

“…Drugs were included into the PLGA/PVA system and investigated for their long-acting potency detectable even after 14 days by a humanized mice model [121,122]. A similar approach was exploited for the incorporation of TAF and elvitegravir, an integrase inhibitor, during the fabrication of devices to be used during vaginal prevention [123,124]. The drug absorption following oral administration were also positively affected by the use of TAF/PGLA loaded NPs, as highlighted by a statistical model study [125].…”