Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Metoprolol in Routinely Treated Japanese Patients

Taguchi, Masato; Nozawa, Takashi; Mizumaki, Kouichi; Inoue, Hiroshi; Tahara, Katsutoshi; Takesono, Chihiro; Hashimoto, Yoshiaki

doi:10.1248/bpb.27.1642

Cited by 30 publications

(48 citation statements)

References 36 publications

(48 reference statements)

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“…13,14) 15) That is, Group 1 consisted of extensive metabolizers with CYP2D6*1/*1, *1/*2, and *2/*2; Group 2 consisted of subjects with CYP2D6*1/*5, *1/*10, *2/*5, *2/*10, and *2/*41; and Group 3 consisted of subjects with CYP2D6*5/*10, *10/*10, and *41/*41 (Table 1). 15,16) In addition, subjects heterozygous for CYP2D6*2/*41 and homozygous for CYP2D6*41/*41 were classified into Group 2 and Group 3, respectively, since it was reported that the CYP2D6*41 allele may be associated with the intermediate metabolizer phenotype. 16,17) In the single-dose (protocol 1) trial, each subject received a single dose of 6 mg aripiprazole (ABILIFY ® tablet) under a fasting condition.…”

Section: Pharmacokinetic Datamentioning

confidence: 99%

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Koue

Kubo

Funaki

et al. 2007

Biological & Pharmaceutical Bulletin

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Aripiprazole is a new antipsychotic developed in Japan, and is prescribed for schizophrenia as a dopamine-serotonin system stabilizer.1,2) The action of aripiprazole is different from that of other typical and atypical antipsychotics; that is, aripiprazole is a potent partial agonist at dopamine D2 and serotonin (5-HT 1A ) receptors and antagonist at 5-HT 2A receptor.3,4) The results of in vitro studies indicated that aripiprazole is mainly metabolized by human cytochrome P450 isozymes CYP3A4 and CYP2D6.5) It has been reported that CYP3A4 and CYP2D6 are metabolic enzymes for numerous compounds, and also that there are many compounds that inhibit these enzymes. Although individual differences in hepatic levels of CYP3A4 enzyme protein have been reported to vary as much as 40-fold, 6) almost no gene mutations affecting CYP3A4 metabolic activity or ethnic differences have been reported. For CYP2D6, however, a number of polymorphisms and the existence of ethnic differences in the types and distribution of polymorphisms have been reported.6,7) The purpose of the present study was to estimate the population pharmacokinetic parameters of aripiprazole in healthy Japanese males, and to evaluate the effects of CYP2D6 polymorphisms and CYP3A4 inhibition on the pharmacokinetics of aripiprazole, and also its unknown (residual) interindividual variability.In the present study, we used the nonlinear mixed-effects model (NONMEM) method designed for the estimation of population pharmacokinetic parameters.8) This method pools data from all individuals but explicitly models and handles the complicated error structure arising from proper accounting of interindividual (h) and intraindividual (e) random effects. The first-order estimation method is the first estimation method available with NONMEM: it handles the error structure of data using first-order Taylor-series expansion in the random effect h, evaluated at the expected values (i.e. hϭ0).9) On the other hand, a newer analysis method designed for the estimation of population parameters, the firstorder conditional estimation (FOCE) method, is available with NONMEM software. 9) That is, FOCE uses first-order expansions for values of the h, but these values are the conditional (Bayesian) estimates of the h, rather than zero. The FOCE method needs much (20-40-fold) longer computational time than the first-order method, but generally gives precise parameter estimates, especially for the analysis of multiple-dose pharmacokinetic data with multiple compartment models. [9][10][11][12] In the present study, therefore, we used the FOCE method to estimate the population pharmacokinetic parameters of aripiprazole, where a two-compartment model with first-order input was applied for data obtained from single-and multiple-dose clinical trials. MATERIALS AND METHODS Pharmacokinetic DataPlasma aripiprazole concentration data for population pharmacokinetic analysis were obtained in two previous studies. 13,14) Briefly, 68 healthy Japanese male subjects, aged 20-32 years old (mean: 23.1) and w...

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Section: Pharmacokinetic Datamentioning

confidence: 99%

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Koue

Kubo

Funaki

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Taguchi et al evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, sex, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype [12]. Nozawa et al showed, that in patients routinely treated with metoprolol, the CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol [13].…”

Section: Resultsmentioning

confidence: 99%

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

Wojtczak

Skrętkowicz

2014

Pharmacological Reports

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The currently used b-blockers differ in their selectivity for b 1 -and b 2 -adrenergic receptors, lipophilicity and route of elimination. Metoprolol is one of the most commonly used b-blockers in the treatment of ischemic heart disease. Metoprolol is a lipophilic b 1 -selective blocker. This drug is well absorbed from the gastrointestinal tract and undergoes extensive distribution in body tissues; it also passes through the blood-brain barrier. The highest plasma concentration value of metoprolol is reached approximately 2 h after administration of a single dose. Metoprolol is extensively metabolized (oxidation) in the liver by the CYP2D6 isoenzyme of cytochrome P450 [2].The gene encoding the CYP2D6 enzyme is highly polymorphic. The CYP2D6 oxidation polymorphism has a major impact on the Background:Metoprolol is the one of the most commonly used b-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Methods: Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50 mg. The blood samples were analyzed for two major defective alleles for CYP2D6 -CYP2D6*4 and CYP2D6*3 -by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). Results: In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 AE SD 36.78 ng/ml vs. mean 168.22 AE SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p = 0.0009). Conclusions: This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma.

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“…The CYP2D6 gene is highly polymorphic with about 80 alleles reported to date [47]. Due to the polymorphic drug metabolizing enzyme, pharmacokinetics of metoprolol vary among individuals [48,49]. This may result in variable responses to the drug, particularly at therapy initiation, given the need to initiate β-blockers at low doses.…”

Section: Genetic Associations With β-Blocker Tolerability In Hfmentioning

confidence: 99%

β-Blocker pharmacogenetics in heart failure

Shin

2008

Heart Fail Rev

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Abstractβ-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients.

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Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Metoprolol in Routinely Treated Japanese Patients

Cited by 30 publications

References 36 publications

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

Nonlinear Mixed Effects Model Analysis of the Pharmacokinetics of Aripiprazole in Healthy Japanese Males

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease

β-Blocker pharmacogenetics in heart failure

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