Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates

Abstract

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf), and decreased function (CYP2D6Decr; i.e., CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n = 77–103) cotreated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; P < 0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9–10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9–10, 33.1% for CYP2D6*9‐10/*9–10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9–10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared with the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9–10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

“…Patients can be classified into CYP2D6 ultrarapid metabolizers (UMs), normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). 3 The CYP2D6 IM group is heterogeneous and can be divided into two subcategories, based on having relatively higher (CYP2D6 IM+) and lower (CYP2D6 IM-) enzyme activity. 4 Knowledge of the CYP2D6 genotype can be utilized for prediction of drug metabolism in vivo.…”

“…The CYP2D6 metabolic capacity in vivo is predominantly genetically determined. Patients can be classified into CYP2D6 ultrarapid metabolizers (UMs), normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) 3 . The CYP2D6 IM group is heterogeneous and can be divided into two subcategories, based on having relatively higher (CYP2D6 IM+) and lower (CYP2D6 IM‐) enzyme activity 4 …”

The Impact of the CYP2D6 “Enhancer” Single Nucleotide Polymorphism on CYP2D6 Activity

“…reported that “taking the enhancer SNP into account when assigning AS with the CYP2D6*2 allele led to more variability being explained in CL 0 compared with conventional AS assignments” in their racially mixed study population 19 . However, this finding may also be explained, at least in part, by having “downgraded” the AS of diplotypes containing CYP2D6*2 and a *41 or *9 allele; for the latter there is mounting evidence supporting that a lower value for AS calculation may more precisely reflect their activity and will therefore likely improve phenotype prediction 35–37 …”

CYP2D6*9 and *41: Does the Activity Value Assigned to these Alleles Need to be Reduced to more Accurately Predict Phenotype?

“…It will thus require many large studies on various CYP2D6 substrates to provide solid evidence for groups, such as the CPIC, to revise their recommendations. In this issue of Clinical Pharmacology and Therapeutics , Jukić et al 6 . provide data needed to fill some of the existing knowledge gaps.…”

“…Figure provides a comparison of the CPIC recommended AS for selected diplotypes and activity predicted by Jukić et al 6 . based on metabolic ratio measurements.…”