Preclinical development and pharmacokinetic assessment in macaques of a multipurpose long-acting injectable suspension containing medroxyprogesterone acetate for contraception and rilpivirine for HIV prevention

Abstract

Depot injections comprising aqueous drug suspensions are widely marketed for long-acting administration of contraceptive progestins and antipsychotics. In recent years, there has been considerable interest in developing similar long-acting injectable products containing antiretroviral drugs for treatment or prevention of HIV infection, culminating in 2020/2021 with the approval of Cabenuva® (which combines the integrase strand transfer inhibitor cabotegravir with the non-nucleoside reverse transcriptase inhibitor rilpivirine for treatment of HIV infection) and Apretude (a cabotegravir extended-release injectable suspension for HIV prevention). Here, we describe formulation and preclinical development of a new multipurpose prevention technology product based on a long-acting injectable aqueous suspension formulation combining micronized medroxyprogesterone acetate (the progestin used in the long-acting injectable contraceptive product Depo-Provera®) and a rilpivirine nanosuspension for HIV prevention. Through the application of an extensive range of analytical methods, we have demonstrated that the resulting combination suspension formulation had a bimodal particle distribution, was stable, was sterilised by gamma irradiation, and provided sustained systemic and vaginal exposure of both drugs over at least one month following intramuscular injection in macaques. Further formulation development will be needed to sustain drug concentrations in the systemic/vaginal compartments over longer time periods, and to consider options for use of alternate antiretroviral drugs.