Lacosamide Pharmacokinetics and Retention in Japanese Patients With Epilepsy: A Retrospective Study on the Influence of Age, Comedications, and Cytochrome P450 2C19 Polymorphism

This retrospective study aimed to identify the genetic and nongenetic factors that influence serum lacosamide (LCM) concentrations and evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on the long-term retention rate of LCM. We analyzed serum samples from 1901 Japanese patients with epilepsy and compared the concentration-to-dose (CD) ratio of LCM among 4 age groups (preschool children, 1-5 years; primary school children, 6-11 years; adolescents, 12-17 years; and adults, ≥18 years). In addition, we performed CYP2C19 genotyping using real-time polymerase chain reaction in 302 patients and classified them into 3 groups: extensive metabolizers (EM: CYP2C19*1/*1), intermediate metabolizers (IM: CYP2C19*1/*2 or *1/*3), and poor metabolizers (PM: CYP2C19*2/*2, *3/*3, or *2/*3). We compared the LCM retention rates between the non-PM (EM and IM) and PM groups using the Kaplan-Meier method. The adult group had the highest mean CD ratio, which was 33.7%, 21.9%, and 7.3% higher than that of preschool children, school children, and adolescents, respectively. The use of enzyme-inducing antiseizure medications (ASMs; ie, phenytoin, phenobarbital, or carbamazepine) reduced the CD ratio by 34.0% in preschool children, 27.3% in primary school children, 24.3% in adolescents, and 27.4% in adults. In adults, the mean CD ratios were 17.7% and 49.0% higher in the IM and PM groups, respectively, than in the EM group. The 3-year retention rate of LCM was higher in the non-PM group than in the PM group (881 vs. 728 days; log-rank test, P < 0.05). Age and the concomitant use of enzyme-inducing ASMs influence LCM pharmacokinetics. In addition, patients with the PM phenotype have a high LCM CD ratio, which may decrease treatment retention. Therapeutic drug monitoring for LCM is a clinically useful method for evaluating pharmacokinetics in individual patients and optimizing the dose of LCM.