Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug–Drug Interactions

Abstract

We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.

Physiologically‐Based Pharmacokinetic Modeling for the Prediction of CYP2D6‐Mediated Gene–Drug–Drug Interactions

“…In preliminary simulations, the existing paroxetine PBPK model from Simcyp library version 17 resulted in the underprediction of paroxetine exposure with the two‐dose regimen used in the dextromethorphan–paroxetine DDI verification study and therefore in the underprediction of DDIs (data not shown), which corroborates with the observed tendency toward underprediction of DDIs between paroxetine and CYP2D6 substrates that was described previously by Marsousi et al . Paroxetine is both a substrate and a strong time‐dependent inhibitor of CYP2D6.…”

“…Similarly, the genotype‐dependent CYP2D6‐mediated intrinsic clearance of duloxetine and paroxetine were estimated from available clinical data in AS1 and AS2 healthy volunteers using the initial models’ CLint CYP2D6 values as starting values for the parameter estimation. A total of 100 iterations around 10‐fold the initial value were interrogated, and a maximum likelihood objective function and expectation maximization as minimization method were used.…”

“…A total of 100 iterations around 10‐fold the initial value were interrogated, and a maximum likelihood objective function and expectation maximization as minimization method were used. As clinical data were obtained in‐house, covariates such as age, sex, weight, height, and CYP2D6 genotype were taken into account for the parameter estimation …”

“…We recently highlighted the differential magnitude of DDIs between homozygous carriers of two fully functional alleles (AS2) and heterozygous carriers of one fully functional with one nonfunctional allele (AS1). Indeed, the AUC ratio of dextromethorphan with paroxetine was about twofold higher in the AS2 subjects when compared with the AS1 subjects …”

“…Drugs with a narrow therapeutic window merit special attention, and the addition of other factors such as liver or kidney diseases may potentiate the impact and clinical relevance of DDIs. In addition, recent evidence suggests an impact of genetic polymorphism on the extent of DDIs . The CYP2D6 activity score (AS) system developed by Gaedigk et al .…”