antiretrovirals could facilitate maintenance and prophylactic treatment in HIV

antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal® technology) in an aqueous carrier. Laser diffraction showed average particle sizes close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5 mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which declining slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20 mg/kg dose (200 nm) did not show relevant differences according to the surfactant used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as a long-acting injectable.

Injectable formulations of antiretroviral drugs for treatment would enhance adherence by reducing pill burden, would avoid the impact of food on drug bioavailability, and would limit the development of resistance by achieving sustained plasma concentrations, just as do injectable contraceptives and anti-psychotic drugs. This study in dogs and mice shows that nanosuspensions may be suitable as long-acting formulations. Interest in their development for pre-exposure prophylaxis (PrEP) purposes will grow if the current PrEP trials show promise.