Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention

Kunal Jhunjhunwala; Charles W Dobard; Sunita Sharma; Natalia Makarova; Angela Holder; Chuong Dinh; James Mitchell; Lin Wang; Junmei Zhang; Sravan Kumar Patel; Walid Heneine; Lisa C Rohan

doi:10.3390/pharmaceutics13081110

Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention

Pharmaceutics. 2021 Jul 21;13(8):1110. doi: 10.3390/pharmaceutics13081110.

Authors

Kunal Jhunjhunwala^{1

2}, Charles W Dobard³, Sunita Sharma³, Natalia Makarova³, Angela Holder³, Chuong Dinh³, James Mitchell³, Lin Wang^{1

2}, Junmei Zhang^{1

2}, Sravan Kumar Patel^{1

2}, Walid Heneine³, Lisa C Rohan^{1

2}

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
² Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
³ Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.

Abstract

Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.

Keywords: HIV prevention; elvitegravir (EVG); non-human primate (NHP); pharmacokinetics (PK); pre-exposure prophylaxis (PrEP); prodrug; rectal microbicide (RM); rectal suppository; tenofovir alafenamide fumarate (TAF); tenofovir diphosphate (TFV-DP).