Abstracts

Rationale: Eslicarbazepine acetate(ESL)is a novel once-daily(QD)AED under clinical development in US for adjunctive therapy in adults with partial-onset seizures. ESL is rapidly&extensively metabolized to eslicarbazepine(major active metabolite),which inhibits voltage-gated sodium channels preferentially in their inactive states.¹ Simvastatin(SIM) is a widely used anti-hyperlipidemic statin that undergoes hepatic hydrolysis to its active metabolite simvastatin ?-hydroxyacid.² This study was conducted to assess effect of ESL on PK of SIM, a known CYP3A4 substrate, and simvastatin ?-hydroxyacid.Carbamazepine is a known inducer of CYP3A4 and it has been shown that CBZ 600mg reduced AUC of SIM(80mg)and simvastatin ?-hydroxyacid by 75%(p<0.001) and 82%(p<0.001),respectively.³Methods: The study was conducted as a single centre,2-way crossover,randomized,open-label study in 24 healthy volunteers.The 2-way crossover phase was constituted by:a)single-dose of 80mg SIM(SIM period)and b)14-day treatment with ESL 800mg QD, in which a single-dose of 80mg SIM was coadministered with the dose of ESL on Day 14(ESL+SIM period),with a washout of 3 weeks between periods. Trough blood samples were collected on days 1,4,6,10,12&14 for determination of ESL.In addition blood samples for assay of SIM and simvastatin ?-hydroxyacid were collected over a 24hour period following administration of SIM either as a single dose or in combination with ESL. Standard noncompartmental methods were used to characterize PK profile of SIM and simvastatin ?-hydroxyacid. Bioequivalence metrics were utilized to compare exposure of SIM and simvastatin ?-hydroxyacid in the absence(ref) and presence(test) of ESL 800mg.Results: Mean SIM C_max decreased 61.1% Test/Reference Point Estimate(PE)=38.88; 90%CI=29.79-50.76), AUC_0-t decreased 53.9%(PE=46.07; 90%CI=38.41-55.26), and AUC_0-? decreased 49.6%(PE=50.43; 90%CI=39.82-63.87) following concomitant administration of ESL. Mean simvastatin ?-hydroxyacid C_max decreased 41.0%(PE=58.97; 90%CI=50.68-68.61), AUC_0-t decreased 51.1%(PE=48.92; 90%CI=43.58-54.92), and AUC_0-? decreased 53.9%(PE=46.04; 90%CI=37.79-56.11) following coadministration of ESL. Post-dose median t_max of SIM and simvastatin ?-hydroxyacid were 1.0 and 4.0 h for ref, and 1.25 and 4.0 h for test, respectively. Thereafter, their plasma concentrations declined in a multiphasic manner with mean apparent terminal t_1/2 of SIM and simvastatin ?-hydroxyacid 7.36 and 9.67 h for ref, and 10.1 and 6.86 h for test, respectively.Conclusions: Based on these findings in adult healthy volunteers, it is concluded that repeated administration of ESL 800mg QD affects PK profile of SIM and simvastatin ?-hydroxyacid with both clinical and statistical significance. Therefore it may be necessary to increase the dose of SIM when co-administered with ESL. Study support by BIAL-Portela;editorial support by Sunovion. References:1.Almeida et al. Neurotherapeutics. 2007;4:88-96.2.Mauro. Clin Pharmacokinet. 1993; 24:195-202.3.Ucar et al. Ren Fail. 2007;29:55-9.