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The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug–gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim®, using a total of 57 plasma concentration–time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound's exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively. [ABSTRACT FROM AUTHOR]

The beta-blocker metoprolol (the sixth most commonly prescribed drug in the USA in 2017) is subject to considerable drug–gene interaction (DGI) effects caused by genetic variations of the CYP2D6 gene. CYP2D6 poor metabolizers (5.7% of US population) show approximately five-fold higher metoprolol exposure compared to CYP2D6 normal metabolizers. This study aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model to predict CYP2D6 DGIs with metoprolol. The metoprolol (R)- and (S)-enantiomers as well as the active metabolite α-hydroxymetoprolol were implemented as model compounds, employing data of 48 different clinical studies (dosing range 5–200 mg). To mechanistically describe the effect of CYP2D6 polymorphisms, two separate metabolic CYP2D6 pathways (α-hydroxylation and O-demethylation) were incorporated for both metoprolol enantiomers. The good model performance is demonstrated in predicted plasma concentration–time profiles compared to observed data, goodness-of-fit plots, and low geometric mean fold errors of the predicted AUClast (1.27) and Cmax values (1.23) over all studies. For DGI predictions, 18 out of 18 DGI AUClast ratios and 18 out of 18 DGI Cmax ratios were within two-fold of the observed ratios. The newly developed and carefully validated model was applied to calculate dose recommendations for CYP2D6 polymorphic patients and will be freely available in the Open Systems Pharmacology repository. [ABSTRACT FROM AUTHOR]