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.
Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically ...active metabolite, O‐desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O‐desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O‐desmethyltramadol was developed and verified in PK‐Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O‐desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O‐desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O‐desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple‐dose administration of tramadol and a single‐dose or multiple‐dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O‐desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O‐desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation.
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.
Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in ...CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol‐O‐methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.
Significant barriers, such as lack of professional guidelines, specialized training for interpretation of pharmacogenomics (PGx) data, and insufficient evidence to support clinical utility, prevent ...preemptive PGx testing from being widely clinically implemented. The current study, as a pilot project for the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment Protocol, was designed to evaluate the impact of preemptive PGx and to optimize the workflow in the clinic setting. We used an 84-gene next-generation sequencing panel that included SLCO1B1, CYP2C19, CYP2C9, and VKORC1 together with a custom-designed CYP2D6 testing cascade to genotype the 1013 subjects in laboratories approved by the Clinical Laboratory Improvement Act. Actionable PGx variants were placed in patient's electronic medical records where integrated clinical decision support rules alert providers when a relevant medication is ordered. The fraction of this cohort carrying actionable PGx variant(s) in individual genes ranged from 30% (SLCO1B1) to 79% (CYP2D6). When considering all five genes together, 99% of the subjects carried an actionable PGx variant(s) in at least one gene. Our study provides evidence in favor of preemptive PGx testing by identifying the risk of a variant being present in the population we studied.
Aims
The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within ...CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6‐mediated metabolism of risperidone in patients with known CYP2D6 genotypes.
Methods
The study included therapeutic drug monitoring (TDM) data from CYP2D6‐genotyped patients treated with risperidone. Risperidone and 9‐hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full‐scan high‐resolution mass spectrometry files was applied for semi‐quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9‐hydroxyrisperidone‐to‐risperidone ratio.
Results
A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9‐hydroxyrisperidone‐to‐risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444‐to‐solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72–0.77, P < .0001).
Conclusion
The present study shows strong, positive correlations between solanidine metabolism and CYP2D6‐mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.
Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of ...single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.
Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a ...better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.
From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.
A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).
This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 ...metabolizer status affected model‐estimated PK parameters of VEN and its active metabolite O‐desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open‐label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O‐desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed‐effect PK model using NONMEM to estimate PK parameters for VEN and O‐desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model‐estimated VEN clearance, VEN exposure, and active moiety (VEN + O‐desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra‐rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN‐related PK parameters, highlighting the importance of genetic factors in personalized medicine.
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