Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes.

BACKGROUND: The aims of this study were to identify the target dose of phenytoin (PHT) and to compare the treatment continuation rate between patients receiving conventional therapy and patients receiving individualized therapy based on genotyping of the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles. The operational definition for the target dose of PHT used in this study was the dose that yielded a steady-state PHT concentration within the range of 15-20 mcg/mL without dose-related adverse effects. METHODS: We investigated 394 samples from 170 Japanese pediatric patients aged 9 months to 15 years to identify factors that influenced the target dose of PHT. We also analyzed the clinical records of 156 patients who commenced PHT therapy at our hospital and retrospectively assessed the time to treatment failure within 1 year after starting PHT therapy. During the study period, 17 patients underwent genotyping at the start of PHT therapy. If the patients had the CYP2C9*3, CYP2C19*2, or CYP2C19*3 alleles, the initial dose of PHT was reduced by 10%-50% according to previous reports. The other 139 patients received conventional PHT therapy. RESULTS: According to multiple regression analysis, the body weight, concomitant use of sulthiame, and the CYP2C9*3, CYP2C19*2, and CYP2C19*3 alleles influenced the target dose of PHT. Our model explained 74% of the interindividual variability of the target dose of PHT. The total withdrawal rate in the individualized therapy group and the conventional therapy group was 23.5% and 33.1%, respectively. The adjusted hazard ratio for withdrawal of PHT therapy in the individualized therapy group was 0.37 (95% confidence interval; 0.12-1.10, P = 0.074). CONCLUSIONS: These findings suggest that genotyping can help to estimate the optimum target dose of PHT and may contribute to avoid intoxication and concentration-dependent adverse effects.

Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy.

OBJECTIVE: The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients. METHODS: A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes. RESULTS: The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (µg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (µg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively. CONCLUSIONS: The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype.

Safety, efficacy, and pharmacokinetics of icatibant treatment in Japanese pediatric patients with hereditary angioedema: A phase 3, open-label study.

We evaluated the safety, efficacy, and pharmacokinetics of subcutaneous weight-adjusted icatibant for the treatment of acute hereditary angioedema attacks in Japanese pediatric patients. Two patients (aged 10-13 and 6-9 years) received icatibant for a total of four attacks. Each attack was abdominal and/or cutaneous and was treated with a single icatibant injection. Mild or moderate injection-site reactions were the only adverse events reported. Time to onset of symptom relief was 0.9-1.0 h. Icatibant was rapidly absorbed, with a pharmacokinetic profile consistent with previous studies. Simulated exposure levels were consistent with non-Japanese pediatric patients. These results support the safety and efficacy of icatibant in Japanese pediatric patients.

4217C>A polymorphism in carbamoyl-phosphate synthase 1 gene may not associate with hyperammonemia development during valproic acid-based therapy.

Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms in the genes encoding carbamoyl-phosphate synthase 1 (CPS1) and N-acetylglutamate synthase (NAGS) were recently reported to be risk factors for the development of hyperammonemia during valproic acid-based therapy. This study aimed to examine the influence of patient characteristics, including polymorphisms in CPS1 4217C>A and NAGS -3064C>A, on the development of hyperammonemia in Japanese pediatric epilepsy patients. The study included 177 pediatric epilepsy patients. The presence of a 4217C>A polymorphism in CPS1 was determined using an allele-specific polymerase chain reaction (PCR)-based method, and the presence of a -3064C>A polymorphism in NAGS was determined using a PCR-based restriction fragment length polymorphism method. Hyperammonemia was defined as a plasma ammonia level exceeding 200 µg/dL. We observed a significant difference between the combination of valproic acid with phenytoin and the development of hyperammonemia in both univariate and multivariate analyses. With regard to the CPS1 4217C>A polymorphism, we did not observe a significant association with the development of hyperammonemia. In conclusion, CPS1 4217C>A polymorphism may not be associated with the development of hyperammonemia in Japanese population.