Dataset Information

Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.

ABSTRACT: Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6-mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype-phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.

SUBMITTER: Frederiksen T

PROVIDER: S-EPMC7818194 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.

Frederiksen Trine T Areberg Johan J Schmidt Ellen E Bjerregaard Stage Tore T Brøsen Kim K

Clinical pharmacology and therapeutics 20200727 1

Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through pop ...[more]

PMID: 32599653

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Project description:IntroductionVortioxetine is an antidepressant primarily metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2D6. A population pharmacokinetic (popPK) model of vortioxetine and its CYP2D6-dependent metabolite was recently published.ObjectiveThe aim of the current study was to assess the predictive performance of the popPK model using vortioxetine concentration measurements from a clinical setting. Furthermore, the study aimed to evaluate the ability of different CYP2D6 phenotype classification systems to provide accurate concentration predictions.MethodsOverall, 1388 patients receiving vortioxetine treatment were identified from a therapeutic drug monitoring (TDM) database in Oslo, Norway; 334 CYP2D6-genotyped patients with 502 serum concentrations of vortioxetine, analysed by a validated ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method, were retrospectively included. The performance of the vortioxetine popPK model was tested on the clinical data from the TDM database.ResultsOverall, the model had a good ability to predict vortioxetine concentrations measured in clinical practice, with a slight tendency to overpredict concentrations. Using simulation-based diagnostics, 76% of the prediction-corrected TDM concentrations were within the 90% prediction interval based on 1000 simulated data sets. Prediction-based diagnostics showed the best performance for CYP2D6 poor and ultrarapid metabolizers, with a median prediction error (MDPE) of 12% and 23%, respectively, while the poorest performance was observed for normal metabolizers, with an MDPE of 66%. In the comparison of different CYP2D6 phenotype classification systems, the use of differentiated activity scores for decreased function alleles did not improve the concentration predictions. Grouping the CYP2D6 genotypes into the four conventional phenotype groups provided predictions closest to the TDM measured concentrations.ConclusionTDM data provide a unique insight into real-world clinical practice with vortioxetine. The tendency of the popPK model to overpredict vortioxetine concentrations measured in TDM may be attributed to several factors, including poor treatment compliance for some patients and, to a lesser extent, lack of information on patient characteristics and misspecified CYP2D6 alleles. To optimize personalized therapy with vortioxetine, real-world clinical data sets originating from different ethnicities need to be studied in the future.

Project description:The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO + DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.

Dataset Information

Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.

Publications

Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.

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