 |
|
|
| |
Long-acting TMC278, a parenteral depot formulation delivering sustained NNRTI plasma concentrations in preclinical and clinical settings
|
| |
| |
Reported by Jules Levin
15th CROI, Feb 3-6, 2008, Boston
G van't Klooster,1 R Verloes,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
Long-acting ARV formulations -
A new paradigm?
Uses of such formulations could include
-- once monthly injectable HAART
-- maintenance of undetectable viral load
-- prophylaxis
Infrequent parenteral dosing offers potential advantages over daily (oral) treatment:
-- sustained concentrations of drugs in plasma
-- may improve adherence to therapy/prophylaxis
-- may avoid gastro-intestinal adverse events
CONCLUSIONS & NEXT STEPS
Injectable long-acting formulations may provide a new paradigm in ARV use
TMC278 LA was demonstrated to be a promising depot formulation
--single doses gave prolonged TMC278 exposure
--in humans, PK profiles and exposures were similar after IM and SC administration
--injections were well tolerated, particularly when administered IM
A novel formulation will contain 300mg/mL TMC278
--evaluation in a single and repeated dose study in healthy volunteers
TMC278: a potent and selective NNRTI
Potent NNRTI in vitro against wild-type and NNRTI-resistant
HIV-1, with an increased genetic barrier to development of resistance1
Potent and sustained efficacy at all doses (25, 75 and 150mg qd) in ARV-naive patients in Phase IIb2
Safe and generally well tolerated2
Potential for antiretroviral therapy in one daily pill or fixed-dose combinations with other agents
Formulation and preclinical methods
Innovative nanosuspension*
-- 100mg TMC278 base per mL
-- particles of pure TMC278, average size of 200nm
-- sterile, stable formulation with neutral pH
TMC278 LA single doses, given as intramuscular (IM)
and subcutaneous (SC) injections to Sprague-Dawley rats and Beagle dogs
PK and injection-site tolerability were evaluated
Tissue concentrations in dogs
High concentrations of TMC278 were observed at the injection site up to 12 weeks in dogs
During the first month, high concentrations were observed in lymph nodes draining the injection site
-- these nodes may act as secondary depots, releasing TMC278 directly into the lymph system
By 24 weeks, the release from the depot was complete, as demonstrated by an absolute bioavailability of essentially 100%
TMC278 LA intramuscular route was better tolerated than the subcutaneous route in dogs
TMC278 LA 200 or 400mg per animal or placebo:
4- and 13-week follow-up
Injection-site reactions (ISRs) were mild to moderate and more frequent with SC than IM administration
Several lymph nodes increased in weight at 4 weeks post dose, consistent with a mild inflammatory response and disproportionate lymph node distribution of nanoparticles
TMC278 LA intramuscular route was better tolerated than the subcutaneous route
No serious adverse events (AEs) or rash
ISRs, but no other AEs, were more common after TMC278 than after placebo injections - no dose response for ISRs
Animal model was predictive for humans regarding ISRs
|
| |
|
|
|
|
|
