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TMC278 long acting - a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteers
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Reported by Jules Levin
IAC Aug 3-8 2008 Mexico City
R Verloes,1 G vanÔt Klooster,1 L Baert,1 F van Velsen,1 M-P Bouche,2 K Spittaels,1 J Leempoels,3 P Williams,1 G Kraus,1 P Wigerinck1
1Tibotec BVBA, Mechelen, Belgium; 2Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium;
3Johnson & Johnson Pharmaceutical Research and Development, Merksem, Belgium
AUTHOR CONCLUSIONS
Injectable LA (long-acting) formulations may provide a new paradigm in ARV use and may facilitate long-term compliance.
TMC278 LA is a promising depot formulation; the concept is viable
-- single 400mg and 600mg doses gave prolonged TMC278 plasma exposure of approximately 20ng/mL after 8 weeks
-- PK exposures were comparable after IM and SC injections
-- favorable safety and tolerability: no serious AEs, grade 3 or 4 AEs or rash
injections were well tolerated, particularly when administered IMg; indurations were more frequent after SC than after IM injections
placebo injections were better tolerated than injections with TMC278 LA; 600mg IMg injections were better tolerated than 600mg SC and than 400mg IMd injections.
Next steps: to perform a multiple-dose trial in HIV-negative healthy volunteers; continue with IM and SC (allowing self-administration) injections.
ABSTRACT
Background: TMC278, a next-generation NNRTI, has shown potent sustained activity against HIV-1 after qd oral doses in a Phase IIb trial of treatment-na•ve patients. Potential future uses of parenteral depot formulations of TMC278 could include maintenance therapy or pre-exposure prophylaxis. We investigated the pharmacokinetics 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 ElanÕs NanoCrystal¨ technology. Pharmacokinetic (PK) and injection-site reactions (ISRs) were evaluated after a single abdominal SC or gluteal IM (IMg) injection in 51 HIV-negative volunteers at doses of 200mg, 400mg and 600mg, or vehicle
(placebo). A further group of nine volunteers received a single 400mg injection into the deltoid (IMd) rather than the 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 12-26 weeks. Mean PK parameters, after 400mg SC and IMg injections, were 70ng/mL and 99ng/mL for maximum plasma
concentration (Cmax), and 57 600 and 61 400ng·h/mL for area under the plasma concentration-time curve from time of administration to Week 12 after dosing (AUC0-Week 12), respectively. Corresponding values after a 400mg IMd 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 IMg route was better tolerated than the IMd route. At the 400mg dose, IMd injection induced more spontaneous pain and pain at touch (6/6 volunteers), albeit of moderate severity, than after IMg 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: A TMC278 LA depot formulation administered in single doses provided prolonged exposure to TMC278 for several months and was well tolerated.
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