Abstracts

Rationale: Stiripentol (STP) is an antiepileptic drug (AED) approved in Japan for adjunctive treatment for tonic or tonic-clonic seizures of patients with Dravet syndrome receiving valproic acid (VPA) and clobazam (CLB). STP inhibits the activity of CYP enzymes such as CYP3A4 and CYP2C19, therefore may elevate concentration of concomitant AEDs. The aim of this study is to investigate the effect of STP on the pharmacokinetics of CLB and N-desmethyl-clobazam (NCLB: an active metabolite of CLB). Methods: We retrospectively reviewed 306 blood samples from 55 patients (aged 1 to 40 years) who received STP, CLB, and other AEDs. We calculated the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB and that of NCLB and studied the effect of CYP2C19 polymorphism. Based on the CYP2C19 genotype, patients were classified into three groups: extensive metabolizers (EM group: CYP2C19*1/*1), intermediate metabolizers (IM group: CYP2C19*1/*2 or *1/*3), and poor metabolizers (PM group: CYP2C19*2/*2, *3/*3, or *2/*3). The study protocol was approved by the ethical committee of National Epilepsy Center (Shizuoka, Japan). Written informed consent was obtained from the patient's guardians enrolled in this study. Results: Firstly, we compared the effect of addition or discontinuation of STP on the CD ratios of CLB and NCLB. In patients without STP, the mean CD ratio of CLB in EM, IM, and PM was 223, 380, and 568 (ng/mL)/(mg/kg), respectively (P < 0.001, ANCOVA adjusted for sex, gender, and body weight). The mean CD ratio of NCLB in EM, IM, and PM was 1,588, 1,949, and 16,722, respectively (p < 0.001). In the EM and IM groups, concomitant use of STP markedly elevated the CD ratio of CLB and NCLB. In the PM group, STP also increased the CD ratio of CLB, but decreased the CD ratio of NCLB. We then investigated the factors that influenced the pharmacokinetics of CLB and NCLB in patients receiving STP. According to multiple regression analysis, body weight and CYP2C19 alleles showed a positive correlation with an increased CD ratio of CLB and NCLB. However, a significant decrease of CD ratio of CLB and NCLB was correlated with an increase of STP dosage irrespective of CYP2C19 polymorphisms. Concomitant use of phenytoin and topiramate reduced the CD ratio of CLB, and use of zonisamide elevated the CD ratio of NCLB. Conclusions: CLB is mainly metabolized by CYP3A4 and partly by CYP2C19 to yield NCLB. NCLB is chiefly metabolized by CYP2C19. Therefore, CYP2C19 phenotypes markedly influence the pharmacokinetics of CLB and NCLB. When a patient commences STP therapy, there may be changes of the pharmacokinetics of CLB and NCLB depending on body weight, CYP2C19 polymorphisms, STP dose and concomitant AEDs. Our findings can be clinically useful for estimating interactions between STP and CLB. Funding: This study was partly funded by a grant-in-aid for Young Scientists (Kakenhi No. 26860123) from the Japanese Ministry of Education, Science, Sports and Culture (MEXT) and Japan Research Foundation for Clinical Pharmacology.