Pharmacokinetics/Genotype Associations for Major Cytochrome P450 Enzymes in Native and First- and Third-generation Japanese Populations: Comparison With Korean, Chinese, and Caucasian Populations

Myrand, S. P.; Sekiguchi, Kanako; Man, MZ; Lin, Xinjie; Tzeng, R‐Y; Teng, C‐H; Hee, Brian; Garrett, May; Kikkawa, Hironori; Lin, C‐Y.; Eddy, SM; Dostalik, J; Mount, Janessa; Azuma, Junichi; Fujio, Yasushi; Jang, Iksu; Shin, Sunghwan; Bleavins,; Ja, Williams; Paulauskis, J.; Wilner, K.

doi:10.1038/sj.clpt.6100482

Cited by 202 publications

(217 citation statements)

References 28 publications

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“…High specificity of classification generates little bias when the exposure-variant genotype in this case-is rare. The prevalence of CYP2D6*4 homozygotes is approximately 5% in populations of European descent, and the prevalence of CYP2D6*10 homozygotes is approximately 18% in populations of Asian descent (71). The bias analysis results are also consistent with evidence from a study in which Dezentje et al (72) analyzed microsatellites flanking the CYP2D6 gene to detect LOH in DNA obtained from tumor-infiltrated tissue.…”

Section: Summary Of Evidencesupporting

confidence: 78%

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Ahern¹,

Hertz²,

Damkier³

et al. 2016

Am. J. Epidemiol.

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Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-Ndesmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumorinfiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women. breast neoplasms; cytochrome P-450 2D6; tamoxifen Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG 1-98, Breast International Group 1-98; CI, confidence interval; CYP2D6, cytochrome P-450 2D6; FFPE, formalin-fixed, paraffin-embedded; FFPE-T, formalin-fixed, paraffinembedded tumor tissue; FFPE-TN, formalin-fixed, paraffin-embedded tumor tissue with nonneoplastic tissue; HWE, HardyWeinberg equilibrium; LOH, loss of heterozygosity; RR, relative risk.

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Section: Summary Of Evidencesupporting

confidence: 78%

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Ahern¹,

Hertz²,

Damkier³

et al. 2016

Am. J. Epidemiol.

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“…The frequency of the CYP2D6*4 minor allele was 24% among recurrent cases and 22% among controls, which compares well with the minor allele frequency reported in reference populations of Caucasians (Sachse et al, 1997;Myrand et al, 2008). As reported above, the conventional adjusted odds ratio associating genetically reduced function (zero or one functional CYP2D6*4 allele) with breast cancer recurrence equaled 1.1 (95% CI 0.81, 1.4).…”

Section: Results and Interpretationsupporting

confidence: 83%

“…We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor positive (ER+) disease treated with tamoxifen for at least one year and matched one control subject per case patient on ER status, tamoxifen treatment, menopausal status, stage, calendar time, and county. We assessed genetic inhibition by genotyping the most prevalent CYP2D6 knockout allele among Caucasians-CYP2D6*4 (Sachse et al, 1997;Myrand et al, 2008). We estimated the odds ratio associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression.…”

Section: Example 1: Cyp2d6 Function and Tamoxifen Effectiveness Motivmentioning

confidence: 99%

Bias Analysis to Guide New Data Collection

Lash¹,

Ahern²

2012

The International Journal of Biostatistics

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Bias analysis serves multiple objectives in epidemiologic data analysis. The objectives most often emphasized are quantification of uncertainty due to systematic errors and reduction in overconfidence by specifying hypotheses that compete with the causal hypothesis. A third objective is the utility of bias analysis to identify strategies for new data collection that will be productive in evaluating the validity of an association. The authors illustrate the value of this objective using two examples. The first example examines the value of comprehensive CYP2D6 genotyping in a study of tamoxifen resistance. Tamoxifen is metabolized primarily by CYP2D6 to more active forms. More than thirty polymorphisms in the CYP2D6 gene reduce its function. We genotyped the most prevalent CYP2D6 polymorphism and found a null association between genotype and breast cancer recurrence in a Danish population. One possibility is that incomplete genotyping of the multiple functional polymorphisms introduced non-differential misclassification and biased the association toward the null. We used bias analysis to evaluate the plausibility of this explanation and to guide a decision about devoting study resources toward more comprehensive genotyping of other polymorphisms in the CYP2D6 gene. The second example examines the association between vitamin K antagonist (VKA) therapy and the incidence of 24 site-specific cancers, using heart valve replacement as an instrumental variable. Earlier studies suggested a protective association between VKA anticoagulants and the incidence of cancer. We observed a null-centered distribution of associations, which may be due to non-differential misclassification of VKA therapy by the instrument. We used bias analysis to evaluate whether this misclassification was likely to explain the null-centered distribution of associations and to guide decisions about conducting a more expensive validation study. In the first example, the bias analysis showed that new data collection would be required to resolve the uncertainty, whereas the second example showed that new data collection was unlikely to be a productive use of scarce study resources.

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“…substrates within genotypes between Caucasians and Asians (Myrand et al, 2008). However, we cannot totally exclude the possibility that the in vitro variability of CYP2C19 abundance was merely applicable to SimCYP, because the validation was based on SimCYP in which variability of some parameters such as CYP3A has been optimized (Cubitt et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Prediction of In Vivo Clearance and Associated Variability of CYP2C19 Substrates by Genotypes in Populations Utilizing a Pharmacogenetics-Based Mechanistic Model

et al. 2015

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It is important to examine the cytochrome P450 2C19 (CYP2C19) genetic contribution to drug disposition and responses of CYP2C19 substrates during drug development. Design of such clinical trials requires projection of genotype-dependent in vivo clearance and associated variabilities of the investigational drug, which is not generally available during early stages of drug development, but is essential for CYP2C19 substrates with multiple clearance pathways. This study evaluated the utility of pharmacogenetics-based mechanistic modeling in predicting such parameters. Hepatic CYP2C19 activity and variability within genotypes were derived from in vitro S-mephenytoin metabolic activity in genotyped human liver microsomes (N = 128). These data were then used in mechanistic models to predict genotype-dependent disposition of CYP2C19 substrates (i.e., S-mephenytoin, citalopram, pantoprazole, and voriconazole) by incorporating in vivo clearance or pharmacokinetics of wild-type subjects and parameters of other clearance pathways. Relative to the wild-type, the CYP2C19 abundance (coefficient of variation percentage) in CYP2C19*17/*17, *1/*17, *1/*1, *17/null, *1/null, and null/null microsomes was estimated as 1.85 (117%), 1.79 (155%), 1.00 (138%), 0.83 (80%), 0.38 (130%), and 0 (0%), respectively. The subsequent modeling and simulations predicted, within 2-fold of the observed, the means and variabilities of urinary S/R-mephenytoin ratio (36 of 37 genetic groups), the oral clearance of citalopram (9 of 9 genetic groups) and pantoprazole (6 of 6 genetic groups), and voriconazole oral clearance (4 of 4 genetic groups). Thus, relative CYP2C19 genotype-dependent hepatic activity and variability were quantified in vitro and used in a mechanistic model to predict pharmacokinetic variability, thus allowing the design of pharmacogenetics and drug-drug interaction trials for CYP2C19 substrates.

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Pharmacokinetics/Genotype Associations for Major Cytochrome P450 Enzymes in Native and First- and Third-generation Japanese Populations: Comparison With Korean, Chinese, and Caucasian Populations

Cited by 202 publications

References 28 publications

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Bias Analysis to Guide New Data Collection

Prediction of In Vivo Clearance and Associated Variability of CYP2C19 Substrates by Genotypes in Populations Utilizing a Pharmacogenetics-Based Mechanistic Model

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