Application of foreign clinical data across geographic regions can accelerate drug development. Drug disposition can be variable, and identification of factors influencing responsible pharmacokinetic/pharmacogenomic approaches could facilitate the universal application of foreign data and reduce the total amount of phase III clinical trials evaluating risks in different populations. Our objective was to establish and compare genotype (major cytochrome P450 (CYP) enzymes)/phenotype associations for Japanese (native and first- and third-generation Japanese living abroad), Caucasian, Chinese, and Korean populations using a standard drug panel. The mean metabolic ratios (MRs) for the four ethnic groups were similar except for a lower activity of CYP2D6 in Caucasians and CYP2C19 in Asians. Genotype, not ethnicity, impacted the MR for CYP2C9, CYP2C19, and CYP2D6; neither affected CYP1A2, CYP2E1, and CYP3A4/5 activities. We conclude that equivalent plasma drug concentrations and metabolic profiles can be expected for native Japanese, first- and third-generation Japanese, Koreans, and Chinese for compounds handled through these six CYP enzymes.
Variation in individual response to statin therapy has been widely studied for a potential genetic component. Multiple genes have been identified as potential modulators of statin response, but few study findings have replicated. To further examine these associations, 2735 individuals on statin therapy, half on atorvastatin and the other half divided among fluvastatin, lovastatin, pravastatin and simvastatin were genotyped for 43 SNPs in 16 genes that have been implicated in statin response. Associations with lowdensity lipoprotein cholesterol (LDL-C) lowering, total cholesterol lowering, HDL-C elevation and triglyceride lowering were examined. The only significant associations with LDL-C lowering were found with apoE2 in which carriers of the rare allele who took atorvastatin lowered their LDL-C by 3.5% more than those homozygous for the common allele and with rs2032582 (S893A in ABCB1) in which the two groups of homozygotes differed by 3% in LDL-C lowering. These genetic effects were smaller than those observed with the demographic variables of age and gender. The magnitude of all the differences found is sufficiently small that genetic data from these genes should not influence clinical decisions on statin administration.
BACKGROUND/AIMS A key consideration for global drug development involves the acceptability of foreign clinical data. Inter‐subject/inter‐ethnic variability has been attributable to extrinsic and intrinsic factors. Clarifying this relationship by PK and pharmacogenomic (PGx) approaches could enhance global drug development and the acceptability of foreign data in different regions. A six‐drug cocktail was used to compare metabolic capacities (MC) of major cytochrome P450 (CYP) enzymes and establish genotype/phenotype associations among Caucasian (C), Chinese (Ch), Korean (K) and Japanese (J) (native, 1st and 3rd generation J) (n=100/group). METHODS Midazolam, caffeine, omeprazole, dextromethorphan, chlorzoxazone, and losartan were used to assess CYP3A4, 1A2, 2C19, 2D6, 2E1, and 2C9, respectively. PGx analyses were conducted and polymorphic loci for each CYP was evaluated. RESULTS Mean MC among the J generations was similar for all six CYP enzymes. Mean MC among the four ethnicities was similar except for lower 2C19 activity in Asians. Mean CYP allelic frequencies for native J were not different from 1st and 3rd generation J, K, and Ch populations but did differ from C at 13 loci. CONCLUSIONS (1) genotype impacted phenotype for CYP2C9, 2C19, and 2D6, (2) genotype had no apparent effects on the observed phenotypes for 1A2, 2E1 and 3A4/5, (3) identical genotypes had similar MC and were independent of ethnicity, and (4) lifestyle factors had negligible effect on genotype/phenotype correlations. Clinical Pharmacology & Therapeutics (2005) 79, P82–P82; doi:
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