Cytochrome P450 2D6 genotype–phenotype characterization through population pharmacokinetic modeling of tedatioxetine

Abstract

The cytochrome P450 (CYP) 2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype‐based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical data set. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6‐dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6‐mediated metabolism was quantified for each subject based on estimates from the final popPK model, and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29), and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (p = 0.02 and p = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to CYP2D6*41 should be revisited, whereas CYP2D6*17 appears to exhibit substrate‐specific behavior. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype–phenotype relationships across substrates.

Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole

“…This is very similar to the results from our two previous analyses of vortioxetine and tedatioxetine using similar methodologies where AS of 0.34 and 0.37, respectively, were estimated for CYP2D6*10. 13,14 Collectively, these results support the recent decision to assign an AS of 0.25 to CYP2D6*10. 8 Large variability in CYP2D6 activity was observed among certain CYP2D6 genotypes, particularly those involving the wildtype allele (e.g., CYP2D6*1/*1, CYP2D6*1/*2, and CYP2D6*1/null).…”

“…In two previous CYP2D6 genotype–phenotype analyses of vortioxetine 13 and tedatioxetine 14 performed using a similar methodology we also found low enzyme activity associated with CYP2D6*17 (AS of 0.17 and 0.01) and CYP2D6*41 (AS of 0.21 and 0.21). Other clinical studies have demonstrated a low activity of CYP2D6*41 in the metabolism of dextromethorphan, 19 tamoxifen, 21 and venlafaxine 28 .…”

“…Two other studies performed with a similar PopPK methodology did not show significant differences in CYP2D6 activity between CYP2D6*1 and CYP2D6*2 in the metabolism of vortioxetine or tedatioxetine, 13,14 respectively, which suggests that the enzyme activity of CYP2D6*2 may be substrate‐dependent.…”

“…12 In two previous studies, we pooled data from clinical studies of CYP2D6 substrates, vortioxetine and tedatioxetine, for two population pharmacokinetic (PopPK) meta-analyses. 13,14 Using a modeling approach, we were able to estimate the CYP2D6-mediated clearance of a large number of individuals with different CYP2D6 genotypes. Similar investigations of other CYP2D6 substrates could contribute to the current knowledge of CYP2D6 genotypephenotype relationships and aid our understanding of substratespecific effects.…”

“…In two previous studies, we pooled data from clinical studies of CYP2D6 substrates, vortioxetine and tedatioxetine, for two population pharmacokinetic (PopPK) meta‐analyses 13,14 . Using a modeling approach, we were able to estimate the CYP2D6‐mediated clearance of a large number of individuals with different CYP2D6 genotypes.…”