Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Mannheimer, Buster; Haslemo, Tore; Lindh, Jonatan D.; Eliasson, Erik; Molden, Espen

doi:10.1097/ftd.0000000000000251

Cited by 33 publications

(35 citation statements)

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“…The O/N ‐desmethylvenlafaxine MR was recently shown to have a high specificity and sensitivity (>85%) in detecting genotype‐predicted CYP2D6 PMs . In the present study on more than 1000 patients, CYP2D6 genotype alone explained 60.7% of the variability in the MR when accounting for significant covariates in the multiple linear regression analysis.…”

Section: Discussionmentioning

confidence: 53%

“…Serum concentrations of O ‐desmethyl‐ and N ‐desmethylvenlafaxine were analysed as a part of TDM of venlafaxine at the Center for Psychopharmacology, Diakonhjemmet Hospital. The analytical method was carried out by use of an ultraperformance liquid chromatography‐mass spectrometry (UPLC‐MS/MS) assay with inter‐ and intra‐day imprecision and inaccuracy parameters <10% .…”

Section: Methodsmentioning

confidence: 99%

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Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Haslemo

Eliasson

Jukić

et al. 2018

Brit J Clinical Pharma

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Aims CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced‐function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. Methods A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O‐desmethyl‐to‐N‐desmethyl‐venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann–Whitney) between carriers of CYP2D6*9–10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non‐coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9–10 and CYP2D6*41 activity scores. Results MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9–10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9–10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45–12.20), 3.55 (2.06–6.10), 1.33 (0.87–2.05) and 0.47 (0.35–0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9–10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9–10. Conclusions CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9–10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.

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Section: Discussionmentioning

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Haslemo

Eliasson

Jukić

et al. 2018

Brit J Clinical Pharma

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“…Furthermore, we compared the ratio of RIS/9-OH-RIS, a parameter that has been demonstrated to be an excellent measure of the CYP2D6 activity. 16,54 We also calculated the dose-adjusted plasma concentration (C/D ratio) for RIS, 9-OH-RIS and AM (RIS + 9-OH-RIS), as the ratio of the plasma concentration of RIS, 9-OH-RIS or RIS + 9-OH-RIS divided by the daily dose of RIS (in [(ng/mL)/mg] …”

Section: Discussionmentioning

confidence: 99%

“…15 Risperidone is mainly metabolized via CYP2D6, and the main active metabolite is 9-hydroxy-RIS (9-OH-RIS, paliperidone). The socalled metabolic ratio (RIS/9-OH-RIS) can be used as a CYP2D6 phenotyping index 16 that is influenced by CYP2D6 polymorphism and CYP2D6 inhibitors. 17 A ratio above 1 (RIS/9-OH-RIS) > 1) is an index of poor CYP2D6 metabolism.…”

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Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

Schoretsanitis¹,

Haen²,

Gründer³

et al. 2016

J Clin Psychopharmacol

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Background: The combination of anticonvulsant mood stabilizers with antipsychotic drugs may lead to clinically relevant drug-drug interactions. The objective of the study was to identify pharmacokinetic interactions of different mood stabilizers on the metabolism of risperidone (RIS) under natural conditions.Methods: A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxy-RIS (9-OH-RIS) of 1,584 adult patients was analyzed. Four groups (n = 1,072) were compared: a control group without a potentially cytochrome interacting comedication (R 0 , n = 852), a group comedicated with valproate (VPA) (R VPA , n = 153), a group comedicated with lamotrigine (LMT) (R LMT , n = 46), and a group under concomitant medication with carbamazepine (CBZ) (R CBZ , n = 21). Dose-adjusted plasma concentrations (C/D ratio) for RIS, 9-OH-RIS and active moiety (AM) (RIS + 9-OH-RIS), as well as metabolic ratios (RIS/9-OH-RIS) were computed.Results: Groups did not differ with regard to the daily dosage (P = 0.46).Differences were detected for the distributions of the C/D ratios for RIS, 9-OH-RIS and AM (P = 0.003, P < 0.001 and P < 0.001, respectively). Differences remained significant after conducting a Bonferroni correction (P = 0.0125). Pairwise comparisons of the concomitant medication groups with the control group revealed significant differences; RIS C/D ratios were significantly higher in the VPA and the LMT group than in the control group (P = 0.013; P = 0.021). However, these differences did not remain significant after Bonferroni correction. In contrast, CBZ-treated patients showed lower dose-adjusted plasma concentrations of 9-OH-RIS (P < 0.001) as well as the AM (P < 0.001) than the control group; this difference survived the Bonferroni correction. Conclusions:The data give evidence for pharmacokinetic interactions between RIS and different anticonvulsant mood stabilizers. Carbamazepine decreased serum concentrations of 9-OH-RIS and the AM when compared with the control group. In case of VPA and LMT, findings were less significant; hints for a weak RIS metabolism inhibition by LMT of unclear clinical significance were found.Key Words: therapeutic drug monitoring, risperidone, carbamazepine, valproic acid, lamotrigine cytochrome P450, interaction, pharmacokinetics (J Clin Psychopharmacol 2016;36: 00-00) G uidelines worldwide recommend the coadministration of second-generation antipsychotics as augmentative therapy to mood stabilizers or vice versa in the treatment of bipolar disorders, especially for the treatment of manic episodes.1-3 Acceptance of this strategy which promises better efficacy 4 despite a higher potential of adverse events 5,6 is reflected in increasing prescription trends. 7 Many pharmacokinetic drug-drug interactions (DDIs) have been identified by therapeutic drug monitoring (TDM) as TDM databases enable evaluation of pharmacokinetic DDIs in a representative population to get an insight into the safety and tolerability of combined psychopharmacological ...

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The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

Lenk

Klöditz

Johansson

et al. 2022

Clin Pharma and Therapeutics

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The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

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Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Cited by 33 publications

References 22 publications

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

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Risperidone and Venlafaxine Metabolic Ratios Strongly Predict a CYP2D6 Poor Metabolizing Genotype

Cited by 33 publications

References 22 publications

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Pharmacokinetic Drug-Drug Interactions of Mood Stabilizers and Risperidone in Patients Under Combined Treatment

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients

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Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients

Significantly lower CYP2D6 metabolism measured as the O/N‐desmethylvenlafaxine metabolic ratio in carriers of CYP2D641* versus CYP2D69* or CYP2D610*: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients