Background:  Infrequent parenteral dosing could facilitate maintenance therapy or prophylactic use of antiretrovirals (ARV). TMC278, a next-generation NNRTI, has demonstrated potent sustained activity against HIV-1 after once-daily oral doses as hydrochloride salt. We have investigated the pharmacokinetics and tolerability after intramuscular and subcutaneous (SC) injections of TMC278 long-acting formulations.

Methods:  TMC278 as a free base and as HCl salt were formulated as sterile nanosuspensions using Elan’s NanoCrystal technology. Pharmacokinetics and injection site tolerability were evaluated after single doses in rats (doses of as much as 20 mg/kg) and dogs (as much as 400 mg per dog). One formulation was studied in 48 HIV-negative volunteers at doses of 200, 400, and 600 mg.

Results:  TMC278 is slowly released from nanosuspension formulations, giving sustained plasma levels for 2 months in rats and as long as 6 months in dogs and humans. In animals, but not in humans, subcutaneous application resulted in more stable plasma levels than intramuscular application, which showed more pronounced initial peaks. High concentrations of TMC278 were observed at the injection site up to 3 months in dogs. However, in 3 to 6 months, the release from the depot was complete as demonstrated by a bioavailability of close to 100%. Within 3 months, the tissue distribution pattern was similar to that previously observed after oral dosing, with 5-fold higher concentrations in lymphoid tissues than in plasma. In dogs, slight swelling with induration, 2 to 3 weeks from dosing, was more frequent after subcutaneous than after intramuscular application. Human plasma concentrations reached a maximum around 3 days, then fell to 60% of these levels by 14 days, before declining very slowly (half-life about 5 weeks) to below 10 ng/mL by 12 to 26 weeks. The pharmacokinetics was dose-proportional and inter-subject variability was low. Typical pharmacokinetic parameters, normalized to a 100-mg dose, were 20.9 ng/mL for C_max and 14,500 ng.h/mL for AUC_0-week12 after both subcutaneous and intramuscular injection. There were no serious adverse events and no premature discontinuations from the study. Injection site reactions consisting of redness, bruising, pain, and sometimes indurations, but no other adverse events, were more common after TMC278 than after placebo injections. The intramuscular route was better tolerated than the subcutaneous route.

Conclusions:  Long-acting TMC278 may be a useful depot formulation since single doses gave prolonged exposure to TMC278 for several months and were well tolerated, particularly when administered intramuscularly.