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.

Possible association between moderate intellectual disability and weight gain in valproic acid-treated patients with epilepsy.

Background: Although patients with moderate intellectual disability (ID) are known to have higher rates of being overweight and obese than those without ID, there are no current data regarding the relationship between ID and weight gain in epilepsy patients treated with valproic acid (VPA).

Patients And Methods: The possible association between moderate ID and an overweight status at the time of initiation of VPA therapy (baseline) was investigated using a logistic regression analysis in 143 patients with epilepsy. Among the 119 nonoverweight patients at baseline, the longitudinal association between moderate ID and the weight status during VPA therapy was retrospectively examined using a Cox hazards regression analysis and the generalized estimating equations approach, while also paying careful attention to associations with other patient characteristics.

Impact of the superoxide dismutase 2 Val16Ala polymorphism on the relationship between valproic acid exposure and elevation of γ-glutamyltransferase in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis.

Background: There has been accumulating evidence that there are associations among γ-glutamyltransferase (γ-GT) elevation and all-cause mortality, cardiovascular diseases and metabolic diseases, including nonalcoholic fatty liver disease. The primary objective of this study was to evaluate the impact of the most common and potentially functional polymorphisms of antioxidant enzyme genes, i.e.

ABCC2 rs2273697 and rs3740066 polymorphisms and resistance to antiepileptic drugs in Asia Pacific epilepsy cohorts.

Aim: To examine the relevance of ABCC2 polymorphisms to drug responsiveness in epilepsy cohorts from the Asia Pacific region.

Materials & Methods: The rs2273697 and rs3740066 polymorphisms were genotyped in 2056 Malaysian (55%), Hong Kong (32%) and Japanese (13%) epilepsy patients.

Results: Significant allele association of rs2273697 was observed in Chinese females with epilepsy, Malaysian Chinese patients with generalized seizure and Japanese patients with partial seizure for the AA versus GG genotype model and Malaysian Chinese patients with generalized seizure for the GA versus GG and autosomal dominant models.

Pregnane X receptor and hepatocyte nuclear factor 4α polymorphisms are cooperatively associated with carbamazepine autoinduction.

Objective: We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy.

Participants And Methods: The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy.

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.

Superoxide dismutase 2 Val16Ala polymorphism is a risk factor for the valproic acid-related elevation of serum aminotransferases.

The association between the superoxide dismutase 2 (SOD2) Val16Ala polymorphism and the serum aminotransferase levels was retrospectively investigated in 207 valproic acid-treated patients with epilepsy. The Val/Val genotype tended to show elevated alanine aminotransferase levels (odds ratio=3.5; P=0.

Atrioventricular block and diastolic dysfunction in a patient with Sanfilippo C.

A 39-year-old woman with Sanfilippo C syndrome was referred to our department for the treatment of bradycardia. An electrocardiogram revealed a second degree atrioventricular block, and pacemaker implantation was performed with the patient under general anesthesia. A transthoracic echocardiogram showed normal left ventricular systolic function, moderate mitral regurgitation due to mitral valve prolapse, and a high E/e' ratio, indicating left ventricular diastolic dysfunction.

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.

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.

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.

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.

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.

Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients.

This study tested the hypothesis that the determinants of mild liver injury are prerequisites for more severe idiosyncratic hepatotoxicity. This study verified whether the possible risk factors for rare idiosyncratic valproic acid (VPA)-induced hepatotoxicity, VPA clearance and/or serum carnitine concentrations are common to those for a mild elevation in transaminases in VPA-treated patients. VPA clearance was calculated in 172 Japanese patients with epilepsy, using a non-linear mixed-effects regression program.

Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gamma-glutamyltransferase in valproic acid-treated patients.

Background: This study was designed to verify whether the glutathione S-transferase (GST) genotypes affect mild hepatotoxicity in valproic acid (VPA)-treated patients.

Methods: The association between the GSTM1 and GSTT1 genotypes, and the levels of aminotransferases and total bilirubin was retrospectively investigated in 149 Japanese epileptic patients treated with VPA.

Results: The adjusted odds ratio (OR) of the GSTM1- vs.

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.

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

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.

ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients.

Objectives: The efflux transporter P-glycoprotein encoded by the ATP-binding cassette (ABC)B1 gene may play a role in drug-resistant epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). Our objective was to investigate the effect of ABCB1 polymorphisms on AED responsiveness and on the pharmacokinetics of carbamazepine (CBZ) in epileptic patients with the indication for CBZ therapy.

Methods: The ABCB1 T-129C, C1236T, G2677T/A and C3435T polymorphisms were genotyped in 210 Japanese epileptics who had been prescribed AEDs, including CBZ, for longer than 2 years.