Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia.
OBJECTIVE
To examine the effect of CYP2D6 genotype on the pharmacokinetics of flecainide, we conducted a population pharmacokinetic analysis of the data collected during routine therapeutic drug monitoring of Japanese patients with supraventricular tachyarrhythmia.


METHODS
Population analysis was performed on retrospective data from 58 patients with normal kidney and liver function treated with oral flecainide for supraventricular tachyarrhythmia. Serum concentrations of flecainide were determined by high-performance liquid chromatography. CYP2D6 genotyping for extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM) alleles was conducted by allele-specific polymerase chain reaction (PCR) and stepdown PCR. WinNonMix was used to estimate oral clearance (CL/F) of flecainide with a one-compartment model for first-order absorption.


RESULTS
Body weight, age, sex, serum creatinine concentration (Scr), and CYP2D6 genotype influenced flecainide pharmacokinetics. The CL/F was affected by age (30% reduction in > or =70 years old) and sex (24% reduction in females). The ratios of CL/F for the five CYP2D6 genotypes were: 1.00 (EM/EM), 0.89 (EM/IM), 0.84 (EM/PM), 0.79 (IM/IM), 0.73 (IM/PM). A model including these five covariates reduced the interpatient variability of CL/F from 32.9% (base model) to 17.8%. Using a Bayesian method we estimated that the CL/F in IMs was significantly lower than in homozygous EMs (0.25+/-0.05 l h(-1) kg(-1) vs. 0.37+/-0.08 l h(-1) kg(-1), P<0.05) among male patients under 70 years old.


CONCLUSIONS
CYP2D6 genotype, even in IMs, as well as body weight, age, sex, and Scr influence flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia.
Doki
Kosuke
K
Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ten-nodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan.
Homma
Masato
M
Kuga
Keisuke
K
Kusano
Kazutomi
K
Watanabe
Shigeyuki
S
Yamaguchi
Iwao
I
Kohda
Yukinao
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005424:Flecainide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D013617:Tachycardia, Supraventricular / Q000188:drug therapy*
D018927:Anti-Asthmatic Agents; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide