|
TMC278 long acting - a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers
R. Verloes1, G. van't Klooster1, L. Baert1, F. van Velsen1, M.-P. Bouche2, K. Spittaels1, J. Leempoels3, P. Williams1, G. Kraus1, P. Wigerinck1
1Tibotec BVBA, Mechelen, Belgium, 2Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium, 3Johnson & Johnson Pharmaceutical Research and Development, Merksem, Belgium
Background: TMC278, a next-generation NNRTI, has shown potent sustained activity against HIV-1 after q.d. oral doses in a Phase IIb trial of treatment-naïve patients. Parenteral depot formulations of TMC278 could be used for maintenance therapy or pre-exposure prophylaxis. We investigated the pharmacokinetics (PK) and tolerability after intramuscular (IM) and subcutaneous (SC) injections of a TMC278 long-acting (LA) formulation.
Methods: TMC278 was formulated as a sterile nanosuspension using Elan’s NanoCrystal® technology. PK and injection-site reactions (ISRs) were evaluated after a single abdominal SC or gluteal IM injection in 51 HIV-negative volunteers at doses of 200, 400 and 600mg, or vehicle (placebo). A further group of nine volunteers received a single 400mg injection into the deltoid rather than gluteal muscle.
Results: TMC278 was slowly released from the injection site. Plasma concentrations of TMC278 reached a maximum around 3 days and then fell biphasically to below 10ng/mL by 12 to 26 weeks. Mean PK parameters, after 400mg SC and gluteal IM injections, were 70 and 99ng/mL for Cmax, and 57,600 and 61,400ng.h/mL for AUC0-week 12, respectively. Corresponding values after a 400mg deltoid IM injection were 80ng/mL for Cmax, and 63,780ng.h/mL for AUC0-week 12. Serious adverse events (AEs) or grade 3 or 4 AEs were not reported. ISRs consisting of redness, bruising, pain and sometimes indurations were more common after TMC278 than after placebo injections. The gluteal IM route was better tolerated than the deltoid IM route. At the 400mg dose, deltoid IM injection induced more spontaneous pain and pain at touch (6/6 volunteers), albeit of moderate severity, than after gluteal IM injection (2/6 volunteers). Based on a greater number of ISRs with the SC versus the IM route, IM injection was better tolerated than SC injection.
Conclusions: TMC278 LA depot formulation administered in single doses provided prolonged exposure to TMC278 for several months and was well tolerated.
|