CYP2D6 Intermediate Metabolizers Research Articles

Genetic Variation in CYP2D6, UGT1A4, SLC6A2 and SLCO1B1 Alters the Pharmacokinetics and Safety of Mirabegron.

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.

Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.

Tamoxifen is an important antiestrogen for the treatment of hormone receptor-positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6-mediated metabolism to 4-OH-solanidine (m/z 414) and 3,4-seco-solanidine-3,4-dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4-OH-solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4-OH-solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4-OH-solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4-OH-solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4-OH-solanidine, and SSDA are diet-derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

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.

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children’s Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

Impact of CYP2D6 and CYP2B6 phenotypes on the response to tramadol in patients with acute post-surgical pain.

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized β coefficients = 0.386 and 0.346, R2 = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized β coefficient = 0.224, R2 = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response.

Effect of CYP2D6 genotype on duloxetine serum concentration.

Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n= 23), intermediate metabolizers (IMs, n= 121), normal metabolizers (NMs, n= 120) and ultrarapid metabolizers (UMs, n= 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p= 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p= 0.01), while women had a 46% higher C/D ratio than men (p= 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.

Pharmacogenetics and phenoconversion: the influence on side effects experienced by psychiatric patients.

Introduction: Preventing side effects is important to ensure optimal psychopharmacotherapy and therapeutic adherence among psychiatric patients. Obtaining the pharmacogenetic profile of CYP2C19 and CYP2D6 can play an important role in this. When the genotype-predicted phenotype shifts because of the use of co-medication, this is called phenoconversion. The aim was to study the influence of the pharmacogenetic (PGx) profile and phenoconversion on side effects experienced by psychiatric patients. Methods: A retrospective cohort study was performed using data from 117 patients from a psychiatric outpatient clinic. Patients were genotyped with a psychiatric PGx panel and side effects were evaluated using the Udvalg for Kliniske Undersølgelser side effects rating scale (UKU). Results: Of all patients, 10.3% and 9.4% underwent phenoconversion (any shift in predicted phenotype) for CYP2C19 and CYP2D6 respectively. No significant associations were found between the phenotype and UKU-score. 75% of the patients with an Intermediate metabolizer (IM) or Poor metabolizer (PM) phenoconverted phenotype of CYP2C19 experienced nausea and vomiting compared to 9.1% of the Normal metabolizer (NM) and Ultrarapid metabolizer (UM) patients (p = 0.033). 64% of the patients with an IM or PM phenoconverted phenotype of CYP2D6 experienced the side effect depression compared to 30.4% NMs and UMs (p = 0.020). CYP2D6 IM and PM patients had a higher concentration-dose ratio than NM patients (p < 0.05). Discussion: This study underlines the importance to consider phenoconversion when looking at a patient's genotype. This is important for a better prediction of the phenotype and preventing possible side effects under a specific psychopharmacotherapy.

Impact of CYP2D6 Genotype on Paroxetine Serum Concentration.

Paroxetine is a selective serotonin reuptake inhibitor metabolized by cytochrome P450 (CYP)2D6. Only small-scale studies have reported the impact of CYP2D6 genotype on paroxetine exposure, and international guidelines differ in their recommendations on whether paroxetine should be administered according to CYP2D6 genotype. To clarify this issue, the aim of the present study was to investigate the impact of CYP2D6 genotype on paroxetine serum concentration in a large population of patients after adjusting for CYP2C19 genotype, age, and sex. Patients from a therapeutic drug monitoring database with records on their paroxetine serum concentrations and CYP2D6 and CYP2C19 genotyping between 2010 and 2021 were included in the study. The impact of CYP2D6 and CYP2C19 genotypes, age, and sex on the paroxetine concentration-to-dose (C/D) ratio was investigated by multiple linear regression analysis. Patients treated with relevant CYP inhibitors or inducers were excluded. In total, 304 patients were included in the study: 17 CYP2D6 poor metabolizers (PMs), 114 intermediate metabolizers (IMs), 168 extensive metabolizers (EMs), and 5 ultrarapid metabolizers. Multiple linear regression analysis showed that CYP2D6 IMs and PMs had 2.2-fold and 3.8-fold higher paroxetine C/D-ratios than extensive metabolizers, respectively ( P < 0.001). Patients who were CYP2C19 IMs (n = 70) or PMs (n = 13) had 1.6-fold higher paroxetine C/D ratio than extensive metabolizers ( P = 0.04). An age ≥65 years was associated with a 2.9-fold increased C/D ratio ( P < 0.001), whereas sex was not significantly associated with paroxetine exposure. The present study showed that CYP2D6 genotype is of significant importance for paroxetine dose adjustments. For CYP2D6 PMs, 25% of the regular paroxetine starting dose may be sufficient, whereas CYP2D6 IMs could receive 50% of the regular dosage. This well-powered study shows that the guidelines should consider the importance of CYP2D6 genotype for personalized dosing of paroxetine.

Does ethnicity impact CYP2D6 genotype-phenotype relationships?

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N=476), (ii) tedatioxetine (N=500), and (iii) vortioxetine (N=1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.

Potential polymorphic CYP1A2 and CYP2D6-mediated pharmacokinetic interactions between risperidone or olanzapine and selected drugs intended to treat COVID-19.

Risperidone/olanzapine are antipsychotics used in Peru to control symptoms of psychosis. The objective was to review the available evidence on potential pharmacokinetic interactions mediated by CYP1A2 and CYP2D6 polymorphic genes between risperidone or olanzapine and selected drugs for the treatment of COVID-19. A bibliographic search was conducted in SciELO and PubMed/Medline. The selection criteria included all types of articles in English and Spanish languages. In this review, the CYP1A2/CYP2D6/CYP3A4 genes that encode their respective enzymes have been described. The olanzapine/risperidone association increases the risk of prolonging the QT interval; chloroquine/hydroxychloroquine decreases metabolism and increases plasma concentration of risperidone; ritonavir decreases metabolism and increases plasma levels of hydroxychloroquine and lopinavir with the risk of prolonging the QT interval of the cardiac cycle and with a tendency to progression towards Torsades de Pointes. Ritonavir increases metabolism and decreases plasma levels of olanzapine. A low incidence of adverse effect was found between risperidone/azithromycin and olanzapine with azithromycin and hydroxychloroquine. Regarding the association of genes: CYP1A2*1D increases and CYP1A2*1F decreases the plasma concentration of olanzapine. Risperidone plasma levels are increased in CYP2D6 intermediate and poor metabolizers compared with normal metabolizers. Other studies indicate no significant association between poor metabolizers of CYP1A2 and CYP2D6 with increased pharmacokinetic parameters. It is concluded that there are potential risks of prolonging the QT interval due to pharmacokinetic interactions mediated by polymorphic genes CYP1A2 and CYP2D6 between risperidone or olanzapine and the drugs selected for the treatment of COVID-19.

Utilization of Pharmacogenomics in Assessment of Tolerability and Efficacy of BTK Inhibitors

Background: Oral inhibitors of Bruton's tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). Despite excellent hematologic responses often seen with this class of medications, discontinuation may occur due to progression or intolerable side effects. It is not fully understood why some patients develop adverse events and discontinue BTKi therapy. A previous study suggested and association between intolerance to BTKi or phosphoinositide 3-kinase (PI3K) inhibitors in CLL patients with genetic polymorphisms in cytochrome P450 enzymes. Polymorphisms in CYP3A and CYP2D6 affect the metabolism of these agents and may lead to higher-than-expected plasma levels, leading to more adverse events. We therefore evaluated the results of pharmacogenomic testing in Veterans treated with BTKi to determine the extent to which pharmacogenomics polymorphisms are associated with response and intolerance to BTKi therapy. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and had undergone pharmacogenetic testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered to veterans at 22 sites across the United States. We retrospectively analyzed clinical factors including time on BTKi, reasons for temporary or permanent discontinuation or dose changes, medical comorbidities, and grade of pertinent side effects associated with BTKi (arrhythmia, hypertension, bleeding, fatigue, arthralgias, rash, diarrhea) as well as use of concomitant medications known to interact with CYP3A or CYP2D6. Results: A total of 61 Veterans were identified, of which 97% (59) were male and 72% (44) were diagnosed with CLL. Of the remaining patients, three were diagnosed with MCL, three with WM/LPL, two with refractory diffuse large B cell lymphoma (DLBCL), one with MZL, and one with monoclonal gammopathy and cold agglutinin disease. Forty-three patients (70.5%) were prescribed ibrutinib, while eight were prescribed acalabrutinib and two zanubrutinib. Twelve patients (20%) permanently discontinued therapy due to intolerance and eight patients (13%) progressed. Another 10 patients temporarily discontinued therapy due to side effects or infection. Median time treated with BTKi was 6.7 months for patients discontinuing for intolerance, 30.1 months for those discontinuing for progression, and 32.9 months for those not requiring discontinuation. The majority of patients who either temporarily or permanently discontinued therapy did so due to new arrhythmia (10 patients), while other complications included infection, pancytopenia, arthralgias, and fatigue. Nearly half of patients were concurrently taking another medication also metabolized through the CYP3A or CYP2D6. Of the 20 patients who progressed or were intolerant of BTKi, 14 (70%) were identified as CYP3A5 poor metabolizers, while 6 (30%) exhibited CYP2D6 intermediate metabolizing function. In comparison, of patients who did not discontinue BTKi, 31 patients (76%) were CYP3A5 poor metabolizers and 11 patients (27%) were CYP2D6 intermediate metabolizers. Conclusions: In our cohort of patients with B cell malignancies who were prescribed BTKi, we identified those who discontinued either due to intolerable side effects or progression at a rate lower than previously reported in the Veteran population. We identified patient with pharmacogenomics polymorphisms that can affect plasma drug levels and are evaluating concurrent use of medication with can affect BTKi metabolism, as well as their effect on time to therapy discontinuation and adverse events. These results will inform the personalized selection of BTKi therapy for patients with B cell malignancies.

CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients.

Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure. Serial plasma samples were collected from 33 GIST patients treated with imatinib 400 mg daily within a prospective clinical trial. Imatinib and nor-imatinib Ctrough were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Genetic polymorphisms with a functional impact on imatinib-metabolizing cytochromes were identified and a GAS was calculated for each gene. A DDI-adjusted GAS was also generated. Imatinib and nor-imatinib Ctrough were measured in 161 plasma samples. CYP2D6 GAS and metabolizer status based on genotype were associated with imatinib and (imatinib + nor-imatinib) Ctrough . CYP2D6 poor and intermediate metabolizers were predicted to have a lower nor-imatinib/imatinib metabolic ratio than normal metabolizers (0.197 and 0.193 vs. 0.247, P = .0205), whereas CYP2C8*3 carriers had a higher ratio than CYP2C8*1/*1 patients (0.263 vs. 0.201, P = .0220). CYP2C9 metabolizer status was inversely related to the metabolic ratio with an effect probably driven by the linkage disequilibrium between CYP2C9*2 and CYP2C8*3. The CYP2D6 DDI-adjusted GAS was still predictive of imatinib exposure. These findings highlight that CYP2D6 plays a major role in imatinib pharmacokinetics, but other players (i.e., CYP2C8) may influence imatinib exposure. These findings could drive the selection of patients more susceptible to imatinib under- or overexposure who could be candidates for personalized treatment and intensified monitoring strategies.

Effects of CYP2D6 genotypes on Plasmodium vivax recurrence after primaquine treatment: A meta-analysis

ObjectivesTo elucidate the relationship between CYP2D6 polymorphisms and Plasmodium vivax recurrence in patients receiving primaquine-based treatment through systematic review and meta-analysis. MethodsWe searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for eligible studies published up to August of 2021. We included studies investigating the associations between CYP2D6 polymorphisms and P. vivax recurrence. We evaluated the pooled odds ratio (OR) and 95% confidence interval (CI). ResultsData from nine studies, including 970 patients, were analyzed. We found that CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), or normal metabolizers slow (NM-Ss) were associated with a 1.8-fold (95% CI, 1.34–2.45; P = 0.0001) higher recurrence of P. vivax than normal metabolizers fast (NM-Fs), extensive metabolizers (EMs), or ultrarapid metabolizer (UMs). Subgroup analysis showed that studies on both Brazilian and Southeast or East Asian individuals had similar results to the main results. Sensitivity analysis by sequentially excluding individual studies also showed robust results (OR range: 1.63–2.01). ConclusionsThis meta-analysis confirmed that CYP2D6 PMs, IMs, or NM-Ss increased the risk of P. vivax recurrence compared to NM-Fs, EMs, or UMs. The results of this study could be used to predict P. vivax recurrence and suggest CYP2D6 genotype-based primaquine dosing.

Comparative analysis of the CYP2D6 metabolic activity and its effect on its effect on the treatment results of primary breast cancer

Background. Standard treatment for hormone receptor-positive breast cancer includes long-term hormone therapy. However, treatment efficacy varies even in homogeneous groups of patients. Tamoxifen is metabolized in the liver, resulting in the production of endoxifen, its active metabolite. Cytochromes P450 (CYP2D6, etc.) play a major role in converting tamoxifen to endoxifen. The CYP2D6 gene is extremely polymorphic and has more than 100 alleles that can encode normal, high, and low metabolic activity or be inactive. Thus, patients can be divided into three groups according to the presence or absence of CYP2D6 gene polymorphisms, namely slow, intermediate, and rapid metabolizers. Objective – to analyze the long-term results of complex treatment of patients with early breast cancer depending on the variability of the polymorphism of the CYP2D6 gene. Materials and methods. We analyzed the frequency of 3 main polymorphisms in the CYP2D6 gene among 89 patients with hormone receptor-positive stage I–II breast cancer who received tamoxifen at a dose of 20 mg/day as adjuvant hormone therapy for 6 months to 9 years. Homozygous carriers of wild-type CYP2D6 allele were assigned to the group of patients with unchanged (normal) metabolism (Group 1) (wt CYP2D6) (n = 64), whereas homozygous and heterozygous carriers of non-functional CYP2D6 alleles were included into the group of patients with slow metabolism (Group 2) (n = 25). Results. Disease progression was observed in 21 (23.6 %) patients with primary operable hormone receptor-positive breast cancer, including 10 women from Group 1 (15.6 %) and 11 women from Group 2 (44 %); the difference between them was statistically significant (p &lt;0.05). Disease progression after combination therapy without chemotherapy was registered in 8 (22.9 %) patients, including 2 (5.8 %) patients with normal metabolism and 6 patients (17.1 %) with slow metabolism (р &lt;0.05). Ten-year relapse-free survival rate was 85.9 % in Group 1 and 63.6 % in Group 2 (р = 0.02). We found no significant difference in overall survival rates between the two groups, which confirmed the results of other studies. Conclusion. The assessment of metabolic activity and its impact on the efficacy of combination treatment for breast cancer is a promising method; however, it requires further research in this area.

The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.

127 Impact of CYP2D6, CYP3A4, and CYP2C9 pharmacogenomic profile on pain relief and adverse events in Canadian children treated with oxycodone and ibuprofen

Abstract Primary Subject area Clinical Pharmacology and Toxicology Background Genomic variation impacts drug pharmacokinetics for commonly used children’s pain medications such as oxycodone and ibuprofen. In order to personalize and best treat children’s pain, how cytochrome enzyme polymorphisms for CYP2D6, CYP3A4, and CYP2C9 impact clinical effectiveness and safety for oxycodone and ibuprofen were studied. Objectives Primary objectives were to evaluate if allelic variations of CYP2D6, CYP2C9, and CYP3A4 would a) alter clinical effectiveness of ibuprofen and oxycodone for pain relief, and b) impact the occurrence of adverse events. Secondary objectives were to determine the degree to which these genetic and other clinical factors influence analgesic effectiveness and safety. Design/Methods This prospective, observational cohort included children aged 4-16 years who were seen in a pediatric emergency department (between June 2010 - July 2014) with an acute fracture and used ibuprofen OR oxycodone for at-home pain management. Saliva samples were obtained prior to discharge, and daily telephone follow-up collected self-reported pain scores, medication use, adverse events, and functional limitations for 3 days. Genotyping identified allelic variants of CYP2D6, CYP3A4, and CYP2C9. Pain was measured using the Faces Pain Scale-Revised. CYP2D6 metabolic phenotypes were determined based on identified variants. Regression analyses were employed to determine relationships between clinical and genomic patient characteristics, pain relief, and adverse events. Results We included 210 children (n=140 ibuprofen, n=70 oxycodone); mean age was 11.1 (±3.5) years, 66.2% were male, and 79.5% self-identified as Caucasian. The median pain reduction in the ibuprofen group was 4 (±2.0) and 4 (±3.5) in the oxycodone group on Day 1 (p = 0.69). Adverse events were experienced by 53.2% of the ibuprofen group and 78.3% of the oxycodone group (p &amp;lt; 0.001). CYP2D6 Intermediate Metabolizers had significantly less pain relief using oxycodone than Extensive Metabolizers (p = 0.04). CYP3A4 variants did not significantly impact pain relief or adverse events. Those with the decreased functioning CYP2C9*2 allele experienced less adverse events compared to the normal functioning allele CYP2C9*1 (p = 0.003) when using ibuprofen. Males (p = 0.035) and all children using non-pharmacological pain strategies (p = 0.02) experienced less pain relief with oxycodone. Conclusion A better understanding of pharmacogenomic variation could help personalize medication choice. Sex and non-pharmacologic pain management impact pain relief with oxycodone, warranting further study to better understand their relationship with opioid pain relief in children.

Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients.

Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations. We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra-rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard-dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain-related hospital encounters. Most patients with cancer (n= 34,675, 56%) received multiple opioids (average 2.8± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n= 105), IM/PMs received a similar number of opioids (3.4± 1.4) as NMs (3.3± 1.9). However, IM/PMs were significantly more likely to experience pain-related hospital encounters compared with NMs, independent of other variables (odds ratio [OR]= 5.4; 95% confidence interval [CI], 1.2-23.6; p=.03). IM/PMs were also more likely to be treated with later-line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR=3.3; 95% CI, 1.1-9.8; p=.03). CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first-line opioids like codeine, tramadol, or standard-dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management. Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6-dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain-related hospitalizations and more frequently required the potent non-CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common "first-line" CYP2D6-metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain-related patient outcomes.

The effect of potent CYP2D6 inhibition on the pharmacokinetics and safety of deutetrabenazine in healthy volunteers

PurposeDeutetrabenazine is a deuterated form of tetrabenazine with a confirmed lower rate of CYP2D6 metabolism of the active metabolites, α- and β-HTBZ. In this study, we assessed the effect of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics and safety of deutetrabenazine and its metabolites.MethodsIn this open-label sequential drug-drug-interaction study, 24 healthy adults who were CYP2D6 extensive or intermediate metabolizers received a single deutetrabenazine 22.5-mg oral dose on days 1 and 11 and a single paroxetine 20-mg oral daily dose on days 4–12. Pharmacokinetics of deutetrabenazine and its metabolites were assessed on days 1–4 and 11–14. Paroxetine trough concentrations were obtained pre-dose on days 9–13. Safety examinations occurred throughout the study.ResultsParoxetine administered under steady-state conditions, increased exposure of the deuterated active metabolites, α-HTBZ (1.2-fold Cmax and 1.8-fold AUC0–∞) and β-HTBZ (2.1-fold Cmax and 5.6-fold AUC0–∞), and correspondingly, 1.6-fold Cmax and threefold AUC0–∞ for total (α + β)-HTBZ. Sixteen subjects reported 45 adverse events and most were mild. Headache was the most common AE reported 8 times by 7 subjects (5 following paroxetine alone; 2 following deutetrabenazine + paroxetine).ConclusionsParoxetine-induced increases in exposure to the active deutetrabenazine metabolites were less than those previously reported for tetrabenazine, a finding expected to reduce the burden of drug interaction. In addition, single doses of 22.5 mg deutetrabenazine, when given alone or in the presence of steady-state paroxetine (20 mg daily), were safe.

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry.

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

Oxycodone findings and CYP2D6 function in postmortem cases

Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.