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

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

Kunal Jhunjhunwala  1   2 , Charles W Dobard  3 , Sunita Sharma  3 , Natalia Makarova  3 , Angela Holder  3 , Chuong Dinh  3 , James Mitchell  3 , Lin Wang  1   2 , Junmei Zhang  1   2 , Sravan Kumar Patel  1   2 , Walid Heneine  3 , Lisa C Rohan  1   2
Affiliations

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

Kunal Jhunjhunwala et al. Pharmaceutics. .

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).

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Conflict of interest statement

W.H. is named on patents and patent applications by the US government on methods of HIV prevention by chemoprophylaxis. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
In vitro dissolution of tenofovir (a–c) and elvitegravir (b–d) from suppositories with three fat-soluble bases (a,b) and three PEG bases (c,d).
Figure 2
Figure 2
In vivo pharmacokinetic assessment following rectal administration of TFV/EVG (40 mg/40 mg) suppositories formulated in witepsol H15 or PEG base in macaques. TFV and EVG levels in plasma (a), rectal fluids (b), and rectal biopsies (c). Dotted line represents the lower limit of quantitation (LLOQ). Red shaded line represents in vitro IC50.
Figure 3
Figure 3
Intracellular TFV-DP levels in rectal biopsies following rectal administration of TFV/EVG (40 mg/40 mg) suppositories formulated in witepsol H15 or PEG base in macaques. Dotted line denotes the lower limit of quantitation (LLOQ). Red shaded line represents levels associated with in vivo protection (82% efficacy).
Figure 4
Figure 4
In vivo pharmacokinetics following rectal administration of PEG suppositories containing TAF/EVG (8 mg/8 mg). Drug concentration versus time plots in rectal fluid (a) and rectal biopsies (b). Dotted line denotes the lower limit of quantitation (LLOQ).
Figure 5
Figure 5
Intracellular TFV-DP levels following rectal administration of PEG suppositories containing TAF/EVG (8/8 mg). Dotted line denotes the lower limit of quantitation (LLOQ). Red shaded line represents levels associated with in vivo protection (82% efficacy).
Figure 6
Figure 6
Intracellular TFV-DP levels in rectal lymphocytes were collected 2 and 24 h post-dosing with PEG suppositories containing TAF/EVG (8/8 mg). Dotted line denotes the lower limit of quantitation (LLOQ). Each color/symbol represents an individual animal.
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