Abstracts

RATIONALE: Antiepileptic drug (AED) development faces formidable hurdles driven by regulatory requirements, the severity of the disease, as well as complex metabolism of most of the established AEDs. The trial cascade of the clinical development plan should follow a rational path. Traditional development plans usually start with experimental placebo-controlled add-on therapy trials in an attempt to meet requirements for approval. However, most of the established AEDs, to which the test anticonvulsant would be added, have enzyme inducing or inhibiting properties. A critical step in this development process is the timely availability of drug-drug pharmacokinetic interaction data before embarking on large placebo controlled add-on trials. The purpose of this study was to evaluate the pharmacokinetic (PK) interactions between retigabine (RGB), a new AED, and one of four established AEDs in an add-on therapy design. The effects of various escalating doses of RGB on the pharmacokinetics of the background AEDs were assessed.
METHODS: Sixty epileptic patients on stable AED monotherapy (valproic acid, topiramate, phenytoin or carbamazepine) participated in this open-titration study. At the initial visit (baseline), the PK of the background AED was obtained. Daily RGB doses (100 or 200 mg, BID or TID) were given as add-on therapy and then increased every 1 or 2 weeks by 200 mg. When maximum tolerability was achieved, the background AED was tapered down weekly by 25% until RGB monotherapy was acheived. Steady-state PK of RGB and the other AEDs were obtained at each dose level. PK parameters were calculated and compared statistically using analyses of variance.
RESULTS: RGB is rapidly absorbed and is eliminated with a terminal half-life of 9 hours. RGB PK is linearly dose-proportional up to a 1200 mg daily dose. The PK of RGB is not altered by valproic acid or topiramate. Similar to the other AEDs, the clearance of RGB is increased by phenytoin and carbamazepine. Further, RGB does not alter the PK of valproic acid, topiramate, phenytoin or carbamazepine.
CONCLUSIONS: This design for ascertaining drug-drug interactions between various AEDs and a new AED is an ideal method in the evaluation of new antiepileptic medications. It permits early determination of the effect of the new agent on the background drug and, vice-versa, at therapeutic doses in epileptic patients. In addition, this design gives open label preliminary safety/efficacy data of the new AED for adjunctive, as well as monotherapy.
Support: Wyeth-Ayerst Research, Radnor, PA
Disclosure: Salary - The following authors work for Wyeth-Ayerst Research:
Ferron, Partiot, Porter, Fritz, Althouse, and Troy Grant - The following authors receive research funds from Wyeth-Ayerst Research: Sachdeo, Biton, and Rosenfeld