Impact of <i>CYP2D6</i> on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol

Waade, Ragnhild Birkeland; Solhaug, Vigdis; Høiseth, Gudrun

doi:10.1111/bcp.14626

Cited by 14 publications

(11 citation statements)

References 18 publications

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“… 13 Recently, authors found evidence that the functional impact of CYP2D6*41 on dose‐adjusted serum levels of patients treated with perphenazine was similar to that of null function alleles. 14 …”

Section: Discussionmentioning

confidence: 99%

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

Frederiksen

Areberg

Schmidt

et al. 2021

CPT Pharmacom & Syst Pharma

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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.

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Section: Discussionmentioning

confidence: 99%

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

Frederiksen

Areberg

Schmidt

et al. 2021

CPT Pharmacom & Syst Pharma

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“…Particularly, CYP2D6 plays a key role in the metabolism of psychiatric drugs, including many antidepressants and antipsychotics, but it is also of importance for antiarrhythmics, antiemetics, β-adrenoceptor antagonists (β-blockers), opioids, and anticancer drugs [ 1 ]. The CYP2D6 gene is highly polymorphic leading to extensive interindividual variability of enzyme activity and systemic exposure of CYP2D6 drugs [ 2 – 4 ].…”

Section: Introductionmentioning

confidence: 99%

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Wollmann

Størset

Kringen

et al. 2023

Eur J Clin Pharmacol

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Purpose Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing. Methods The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts. Full-scan high-resolution mass spectrometry data files of previously analyzed serum samples were reprocessed for identification and quantification of solanidine and seven metabolites. Metabolite-to-solanidine ratios (MRs) of the various solanidine metabolites were calculated prior to performing receiver operator characteristic (ROC) and multiple linear regression analyses on the test cohort. The MR thresholds obtained from the ROC analyses were tested for the prediction of CYP2D6 PMs in the validation cohort. Results In the test cohort, the M414-to-solanidine MR attained the highest sensitivity and specificity parameters from the ROC analyses (0.98 and 1.00) and highest explained variance from the linear models (R2 = 0.68). Below these thresholds, CYP2D6 PM predictions were tested in the validation cohort providing positive and negative predictive values of 100% for the MR of M414, while similar values for the other MRs ranged from 20.5 to 73.3% and 96.7 to 99.3%, respectively. Conclusion The M414-to-solanidine MR is an excellent predictor of the CYP2D6 PM phenotype. By measuring solanidine and metabolites using liquid chromatography-mass spectrometry in patient serum samples, CYP2D6 PMs can easily be identified, hence facilitating the implementation of precision dosing in clinical practice.

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“…However, the difference may also be due to the naturalistic setting of the data sets in this study, compared with a controlled population. Both perphenazine and zuclopenthixol have been found to be strongly influenced by the metabolic status of the CYP2D6 enzyme [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. For these drugs, patients prescribed a standard dosage and who are either poor metabolisers or subject to drug interactions are expected to harbour a higher serum concentration.…”

Section: Discussionmentioning

confidence: 99%

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

Larsen¹,

Hoffmann-Lücke

Aaslo

et al. 2023

Pharmaceutics

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Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories.

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Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol

Cited by 14 publications

References 18 publications

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

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

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

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