Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments

Abstract

Bictegravir (BIC) and tenofovir alafenamide fumarate (TAF), two potent anti-HIV drugs, had been nanoformulated (nBIC-TAF) to achieve once-a-month PrEP coverage. In-vivo mouse experiments for nBIC-TAF exhibited favorable subcutaneous (SC) pharmacokinetics. To probe the clinical suitability of the nBIC-TAF, as the next step, we intend to study nBIC-TAF in non-human primates (NHP), as the best preclinical model to foster clinical trials. Before entering an expensive NHP study, however, we seek to improve our a priori understanding about nBIC-TAF in higher species, having just mouse data. The mechanism-based pharmacokinetic modeling (MBPK) has been used as an appropriate method for pharmacokinetic modeling and interspecies scaling for nanoformulations. Via the use of MBPK, in this work, we created a model for nBIC-TAF able to predict plasma concentration-time curves in NHP. BIKTARVY is a daily oral combination of BIC, TAF, and emtricitabine (Gilead Science, CA), approved for HIV therapy. Using BIKTARVY equivalent dosages (from their NHP studies), we predicted that, following just one SC dose of nBIC-TAF in NHP, both BIC and tenofovir will have detectable and above in vitro efficacy levels for 28 days. Furthermore, the MBPK was able to provide a mechanistic explanation regarding the long-acting mechanism characterizing nBIC-TAF: nanoparticles stores in the SC space from which drugs slowly dissociate. Dissociated drugs in the SC space then buffer the plasma pool over time, yielding an extended-release effect in the plasma. Overall, we predicted for nBIC-TAF a promising long-acting pharmacokinetic in NHP, potentially usable as monthly PrEP. These results will help investigators to gain confidence for facing regulatory submissions at early stages.

A Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure Prophylaxis

“…However, protection studies (Fig. 2 and Table 1), as predicted in nonhuman primates, lasting 28 days (57) or longer require further investigation to confirm the HIV-1 PrEP efficacy of BIC1TAF NP.…”

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles

“…Our knowledge regarding the PK of TLC-ART 101 and more generally that of DcNP was gained through a stepwise process. We began with a series of PK experiments in NHP that led to the development of mechanism-based compartmental models (i.e., the MBPKs), 7,10,14 through which we arrived at the crucial working hypothesis that DcNP form a drug depot in the lymphatic system rather than in the injection site as it is featured in most of the long-acting injectables in development (e.g., ref 34 ). We previously conducted a fluorescenceimaging study with indocyanine green (ICG) tagged lipid nanoparticles (i.e., labeled empty DcNP) in mice to provide detailed information on the distributive kinetics of DcNP across the lymphatic network following SC injection in the hind paw (ref 35 and unpublished material).…”

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture

“…The current PBPK model evolved from our MBPK models, which were useful in explaining the complex pharmacokinetic profiles of LPV, RTV, and TFV nanoformulated in DcNP. 6,9,11,50,51 One major feature of the model was the inclusion of three distinct lymphatic transit pathways that route the dose from the SC injection site to the systemic circulation in successive phases. The PBPK modeling effort reported in the present two-part series should allow us to relate the complex pharmacokinetic mechanisms of DcNP to the local and regional lymphatic physiology.…”