Takateru Ishitsu

Association between SCN1A polymorphism and carbamazepine-resistant epilepsy

AIMS To establish whether the SCN1A IVS5-91 G > A polymorphism of the SCN1A gene, which encodes the neuronal sodium channel alpha subunit, affects responsiveness to the antiepileptic drugs (AEDS) carbamazepine and/or phenytoin. METHODS SCN1A IVS5-91 G > A polymorphism was genotyped in 228 Japanese epileptic patients treated with AEDs. The association between AED responsiveness and the polymorphism was estimated by logistic regression analysis, adjusting for clinical factors affecting the outcome of AED therapy. RESULTS The frequency of the AA genotype was significantly higher in carbamazepine-resistant patients (odds ratio, 2.7; 95% confidence interval (CI), 1.1, 7.1) and was insignificantly higher in AED-resistant patients. CONCLUSIONS This is the first report demonstrating an association between the SCN1A polymorphism and carbamazepine-resistant epilepsy.

Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity

UNLABELLED The aim of this study is to verify whether the combination of glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, which is a candidate genetic risk factor for troglitazone-induced liver failure, is common to that for the carbamazepine-induced mild hepatotoxicity. PATIENTS & METHODS The genotypes of GSTM1 and GSTT1, and microsomal epoxide hydrolase-3 and -4, were determined in 192 Japanese epileptics treated with carbamazepine. RESULTS The GSTM1 null (GSTM1-) and GSTT1 null (GSTT1-) genotypes in the subjects were 55.7 and 39.6%, respectively. The alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated in 46 (24.0%) and 62 (32.3%) cases, and the mean values were approximately 2.3- and 1.8-times higher than the upper limit of normal levels, respectively. The levels of ALT and AST were significantly higher in GSTM1- than in GSTM1 present (GSTM1+) genotypes (p = 0.007 and 0.004, respectively). The level of ALT was significantly higher in GSTM1-/T1- than in GSTM1+/T1- and GSTM1+/T1+ (p = 0.01 and 0.01, respectively), and that of AST was significantly higher in GSTM1-/T1- and GSTM1-/T1+ than in GSTM1+/T1+ (p = 0.02 and 0.003, respectively). The microsomal epoxide hydrolase genotype did not influence the hepatotoxicity. CONCLUSION These findings suggested that GSTM1- rather than GSTM1-/T1- was a risk factor for carbamazepine-induced mild hepatotoxicity.

Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy

BACKGROUND Clobazam-induced adverse reactions have been reported in cases with CYP2C19 defective allele(s). However, the relevance of the CYP2C19 genotypes to clobazam therapy remains to be clarified. METHODS The association between CYP2C19 genotypes and the antiepileptic and adverse effects of clobazam was retrospectively investigated in 110 Japanese subjects, in relation to clobazam and N-desmethylclobazam (N-clobazam) concentrations. RESULTS There were 41 (37.3%) homozygous extensive metabolizers (EMs), 44 (40.0%) heterozygous EMs, and 25 (22.7%) poor metabolizers (PMs). The response rate was significantly greater in PMs and heterozygous EMs than homozygous EMs with a gene-dose effect (65.2, 47.6 and 33.3%, respectively), and the adjusted odds ratio (95% CI) of PM versus homozygous EMs was 9.88 (2.47-39.56; p = 0.001). However, the genotypes did not affect the development of tolerance or adverse reactions, although the incidence of some adverse symptoms was insignificantly higher in PMs. The N-clobazam concentration (microg/ml) increased with the number of CYP2C19-defective alleles (0.92 +/- 0.61, 2.14 +/- 1.69 and 7.70 +/- 6.04, respectively; p < 0.001), while the clobazam concentration was 1.5-fold greater in those with at least one variant. CONCLUSION CYP2C19 genotype had an impact on the efficacy of clobazam, thus indicating that N-clobazam plays an important role in long-term clobazam therapy.

Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese.

Abstract: A nonlinear mixed-effect modeling (NONMEM) program was used to evaluate the effects of cytochrome P450 (CYP) 2C9 and CYP2C19 polymorphisms on the phenobarbital (PB) population clearance for Japanese epileptics. The pharmacokinetics of the 260 PB concentrations at a steady-state obtained from 79 patients was described with a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight (BW), age, gender, PB daily dose, CYP2C9 and CYP2C19 genotypes, the coadministered antiepileptic drugs (AEDs), and complications. The final model of PB apparent clearance was as follows: where CL = the clearance of PB; CYP2C9*1/*3 = 1, otherwise 0; VPA = 1 if valproic acid is coadministered, otherwise 0; PHT = 1 if phenytoin is coadministered, otherwise 0; SMID = 1 if complications of severe or profound mental retardation with a significant behavior impairment are presented, otherwise 0; and &eegr;CL = the independent random error distributed normally with the mean zero and variance equal to ωP2. The total clearance of PB decreased by 48% in patients with CYP2C9*1/*3 genotype in comparison with those with CYP2C9*1/*1 genotype (P < 0.001). An effect of CYP2C19 polymorphisms was not detected. To our knowledge, this is the first report to demonstrate that the CYP2C9 genotype affects the PB metabolism in routine care, but the results should be further verified in other ethnic populations.

ABCC2 haplotype is not associated with drug‐resistant epilepsy

Several studies have investigated the association between the ABCB1 polymorphism and drug‐resistant epilepsy. However, the effect of ABCC2 polymorphisms on anti‐epileptic drug (AED) responsiveness remains unknown. The ABCC2 polymorphisms have been genotyped in 279 Japanese epileptic patients treated with AEDs. The association between the AED responsiveness and the polymorphisms was estimated by a haplotype‐based analysis. No genotype or haplotype was associated with drug‐resistant epilepsy. On the other hand, the delGCGC haplotype at G‐1774delG, C‐24T, G1249A and C3972T was over represented among the epileptic patients with a complication of mental retardation in comparison with those without (32.4% vs 22.0%; P = 0.009); and the G‐1774delG allele was also associated with mental retardation (P = 0.03). No association between the ABCC2 genotypes or haplotypes, and the responsiveness of AEDs was observed, although this finding was inconclusive because of the small sample size.

Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy

o the Editor: In recent issues of the Journal the antithetical effects of ytochrome P450 (CYP) 3A5 genotypes were reported. He t al indicated that none of the CYP3A5 gene variants howed any significant influence on oral midazolam clearnce. Mouly et al demonstrated the mean apparent oral learance (CL/F) of saquinavir in carriers of CYP3A5*1 alele(s) to be almost twice as high as that in noncarriers. We investigated the influence of CYP3A5*3 polymorphism n carbamazepine pharmacokinetics in Japanese patients with pilepsy (Table I) using a nonlinear mixed effect regression rogram, WinNonMix (version 2.0.1; Pharsight, Mountain iew, Calif). A 1-compartment model was used, and a regresion model was developed by use of the forward-inclusion and ackward-elimination method. The covariates evaluated were as ollows: age; body weight (BW); sex; carbamazepine daily dose; oadministration of valproic acid, phenytoin, or phenobarbital or some combination thereof); and CYP3A5*3 genotype. In a forward-inclusion analysis we incorporated the BW in he CL/F model because BW and age correlated closely. Sex and he coadministration of valproic acid did not improve the model. hen the effect of the CYP3A5 genotype was adjusted for BW, arbamazepine daily dose, and phenytoin or phenobarbital codministration in the full model, the CL/F in the CYP3A5*3/*3 C

Population estimation regarding the effects of cytochrome P450 2C19 and 3A5 polymorphisms on zonisamide clearance.

We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. ηCL is the independent random error distributed normally with the mean zero and variance equal to ωCL2. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.

Update on the genetic polymorphisms of drug-metabolizing enzymes in antiepileptic drug therapy

Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.

Effects of CYP2C19 and P450 oxidoreductase polymorphisms on the population pharmacokinetics of clobazam and N-desmethylclobazam in japanese patients with epilepsy.

Background: Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N-CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19. Meanwhile, P450 oxidoreductase (POR) is the obligatory electron donor to all microsomal CYP enzymes. The aim of this study was to evaluate the impact of the CYP2C19 and POR genotypes on the pharmacokinetic parameters of CLB and N-CLB. Methods: This retrospective study included 85 Japanese patients with epilepsy who were treated with CLB. CYP2C19*2, *3, and P450 oxidoreductase (POR) *28 (rs1057868C>T) polymorphisms were evaluated. A total of 128 steady-state concentrations for both CLB and N-CLB were collected from the patients. A nonlinear mixed-effects model identified the pharmacokinetics of CLB and N-CLB; the covariates included CYP2C19 and POR genotypes, weight, gender, daily CLB dose, and coadministered antiepileptic drugs. Results: Among the 85 patients, the allele frequencies of CYP2C19*2, CYP2C19*3, and POR*28 were 27.6%, 12.9%, and 41.2%, respectively. A one-compartment model with first-order absorption and/or elimination showed that the clearance of CLB and N-CLB was significantly lower by 18.1% and 84.9%, respectively, in the CYP2C19 poor metabolizers compared with the homozygous extensive metabolizers. The CLB clearance was 44% higher in subjects homozygous for the POR*28 T allele than in those homozygous for the POR*28 C allele, although the genotypes did not affect the N-CLB clearance. The concomitant use of phenobarbital, phenytoin, and zonisamide significantly affected the CLB clearance, whereas that of carbamazepine, phenytoin, and valproic acid affected the N-CLB clearance. The weight also significantly influenced the CLB clearance and volume of distribution of both CLB and N-CLB. Conclusions: Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.

Determination of the optimal concentration of valproic acid in patients with epilepsy: A population pharmacokinetic-pharmacodynamic analysis

Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy.