Summary
Carisbamate (RWJ-333369) is a novel neuromodulator, initially developed by SK Biopharmaceuticals (Fairlawn, NJ), under development by Johnson & Johnson Pharmaceutical Research and Development (La Jolla, CA). Carisbamate displays high potency in a broad range of rodent seizure models at doses well below those that produce CNS toxicity. Its mechanism of action has not been elucidated. Acute and chronic nonclinical toxicological studies have not revealed any significant abnormalities other than dose-related CNS toxicity. It is extensively metabolized, chiefly through glucuronidation and oxidation of the aliphatic side chain. There is little evidence of CYP metabolism. It has linear pharmacokinetics. Its clearance is increased by carbamazepine and to a lesser degree by oral contraceptives. Carisbamate slightly increases the clearance of valproic acid and lamotrigine. The most common adverse events in humans are headaches, dizziness, and somnolence, generally mild to moderate, occurring at doses of 1000 mg/day or more. A recently completed phase 2 study for adjunctive use in partial onset seizures showed efficacy at a dose that was well tolerated.
Key Words: Epilepsy, antiepileptic drug, rodent seizure models, pharmacokinetics, drug interactions
References
- 1.White HS, Srivastava A, Klein B, et al. The novel investigational neuromodulator RWJ 333369 displays a broad-spectrum anticonvulsant profile in rodent seizure and epilepsy models (abstract) Epilepsia. 2006;47(suppl 4):200–200. [Google Scholar]
- 2.Nehlig A, Rigoulot M-A, Boehrer A. A new drug, RWJ-333369, displays potent antiepileptic properties in genetic models of absence and audiogenic epilepsy (abstract) Epilepsia. 2005;46(suppl 8):215–215. [Google Scholar]
- 3.Grabenstatter HL, Dudek FE. The use of chronic models in antiepileptic drug discovery: The effect of RWJ-333369 on spontaneous motor seizures in rats with kainite-induced epilepsy (abstract) Epilepsia. 2004;45(suppl 7):197–197. doi: 10.1111/j.0013-9580.2005.13404.x. [DOI] [PubMed] [Google Scholar]
- 4.Francois J, Ferrandon A, Koning E, Nehlig A. A new drug, RWJ-333369, protects limbic areas in the lithium-pilocarpine model (lipilo) of epilepsy and delays or prevents the occurrence of spontaneous seizures (abstract) Epilepsia. 2005;46(suppl 8):269–270. [Google Scholar]
- 5.Mannens GSJ, Hendricks J, Janssen C, et al. The absorption, metabolism and excretion of the novel neuromodulator RWJ-333369 in humans. Drug Metab Dispos 2006 (in press). [DOI] [PubMed]
- 6.Yao C, Chien S, Doose DR, Novak J, Bialer M. Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369, following single and multiple doing to humans. Epilepsia. 2006;11:1822–1829. doi: 10.1111/j.1528-1167.2006.00814.x. [DOI] [PubMed] [Google Scholar]
- 7.Chien S, Yao C, Mertens A. Lack of clinically significant pharmacokinetic drug interactions between RWJ-333369 and valproate or lamotrigine. Epilepsia. 2005;46(suppl 8):173–173. [Google Scholar]
- 8.Chien S, Bialer M, Solanki B. Pharmacokinetic interaction study between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine in healthy subjects. Epilepsia. 2006;11:1830–1839. doi: 10.1111/j.1528-1167.2006.00815.x. [DOI] [PubMed] [Google Scholar]