CYP2D6 Phenotype Research Articles

Role of CYP2D6 polymorphisms in tramadol metabolism in a context of co-medications and overweight.

Very few quantitative data exist on tramadol metabolites, which hampers our understanding of their role in efficacy and safety of tramadol. We aimed to provide quantitative data on tramadol and its 5 main metabolites in a patient cohort and to determine whether metabolite ratios can be predictive of a CYP2D6 metabolism phenotype. We also aimed to investigate the influence of co-medications and patient profile (BMI, glycemia, lipid levels) on tramadol metabolite ratios. Overall, 37 patient samples from the CONSTANCES cohort contained tramadol and its 5 metabolites. Mean concentrations found tramadol at 343.2±223.2 μg/L, M1 at 62.4±41.4 μg/L, M2 at 210.0±272.3, M3 at 1.76±3.0 μg/L, M4 at 1.8±2.8 μg/L and M5 at 31.8±28.4 μg/L. The most frequent CYP2D6 phenotype was extensive metabolizers (51.3%), followed by intermediate metabolizers (24.3%) and poor metabolizers (10.8%). CYP2D6-inhibiting co-medications impacted tramadol metabolism independently of CYP2D6 metabolism phenotype. Lipid parameters and glycemia were significantly associated with changes in tramadol metabolic ratios. Metabolic ratios are not sufficient to determine the CYP2D6 metabolic phenotype in patients. CYP2D6 inhibitors and obesity/NAFLD/diabetes impact tramadol metabolism. These factors are likely to impact the analgesic efficacy and safety profile of tramadol, justifying the need for further studies in this area.

CYP2D6 Phenotype and Breast Cancer Outcomes: A Bias Analysis and Meta-Analysis.

We evaluated the impact of systematic bias due to loss of heterozygosity (LOH) and incomplete phenotyping in studies examining the relationship between CYP2D6 variants and breast cancer recurrence among women treated with tamoxifen. We performed a systematic review of the literature on tamoxifen, CYP2D6 variants, and breast cancer recurrence. A quantitative bias analysis was performed to adjust for LOH and incomplete phenotyping. Bias-adjusted results were then combined in a meta-analysis. Thirty-three studies informed the bias analysis and meta-analysis on CYP2D6 variants and breast cancer recurrence and/or mortality. An unadjusted meta-analysis suggested increased risk of recurrence and/or mortality for poor relative to normal metabolizers [RR = 1.28; 95% simulation interval (SI), 1.04-1.58] with substantial heterogeneity (I2 = 27%; P for heterogeneity = 0.07). Adjusting for LOH and incomplete genotyping resulted in a slight change in the effect estimate and a decrease in heterogeneity (RR = 1.34; 95% SI, 1.10-1.63; I2 = 0%; P for heterogeneity = 0.17). Intermediate metabolizers had a slightly increased risk of recurrence and/or mortality relative to normal metabolizers (RR = 1.15; 95% SI, 1.00-1.34; I2 = 0%; P for heterogeneity = 0.89). Adjusting for biases such as LOH and incomplete genotyping reduced observed heterogeneity between studies. Individuals with poor CYP2D6 phenotypes were at increased risk for breast cancer outcomes compared with those with normal phenotypes. Reduction in CYP2D6 activity was associated with an increased risk of breast cancer recurrence and/or mortality, and results underscore the importance of quantitatively adjusting for biases when aggregating study results.

Do CYP2D6 polymorphisms affect the efficacy and toxicity of flecainide? A cohort study

Abstract Background The CYP2D6 enzyme, coded by the CYP2D6 gene, is the primary metabolic pathway for flecainide.(1,2) Over the years, studies on how different variants of this gene affect flecainide metabolism and efficacy have yielded contradictory results.(3–7) This is likely due to the fact that CYP2D6 pharmacogenetic classifications were not standardized until 2017.(8,9) Purpose To date, there has been no published study using a standardized classification to assess the efficacy and toxicity of flecainide across different CYP2D6 phenotypes; therefore, we decided to study this. Methods We conducted a cohort study with data collected through indirect methods, blinding all parties involved except the statistician. We identified patients with flecainide prescriptions (100 mg/12 h) and follow-up in our health area (n=450,136 people) between 2017 and 2021. A primary combined endpoint composed of initial inefficacy and early toxicity was pre-set, and a secondary combined endpoint of toxicity or inefficacy during follow-up. Results 104 patients met the criteria and agreed to participate: 38 (36.5%) intermediate metabolizers, 52 (50%) normal metabolizers, 2 (1.9%) could not be classified with certainty (compatible with intermediate or normal metabolizers), 7 (6.7%) poor metabolizers, 4 (3.8%) ultra-rapid metabolizers, and 1 (1%) possible hybrid. Intermediate and normal metabolizers showed an almost superimposable incidence of the primary endpoint (28,9% vs 28,8%, p=0.99), early inefficacy (21,6% vs 17,4%, p=0.97) and early toxicity (13,2% vs 13,3%, p=0.72). No significant differences were observed in multivariate analysis (p=0.76, picture 1) or in a combined endpoint of toxicity or inefficacy during follow-up (p=0.58, Kaplan-Meier in picture 2). Differences were seen in the primary endpoint when comparing poor metabolizers to the rest of the sample, although they did not reach statistical significance (p=0.07), likely due to the small number of patients in this group (n=7, absolute risk reduction -32%; 95% confidence interval: -41% to -23%). Conclusions Using the standardized classification for CYP2D6 pharmacogenetics, no statistically significant differences were detected between the two largest groups, intermediate and normal metabolizers. It is possible that better results are achieved in poor metabolizers. Based on these results, it is worth questioning whether, in an attempt to minimize the risk of flecainide toxicity, doses that are subtherapeutic in all groups except slow metabolizers have been used unknowingly.

Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing.

Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine. We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development. Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers. Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine.

CYP2D6 activity in patients with metastatic breast cancer treated with single agent tamoxifen: results from ECOG-ACRIN E3108.

In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes. Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3month post registration plasma samples (Quest Diagnostics). From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9months and 6.9months, respectively. Median PFS was 11.1 and 13.8months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml). We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS. NCT01124695 (registered May 14, 2010).

Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.

Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Erythromycin increased the area under the curve (AUCτ) and peak concentration (Cmax) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (Tmax). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Use of CYP2D6 substrates and inhibitors during pain management with analgesic opioids: Drug-drug interactions that lead to lack of analgesic effectiveness

BackgroundSeveral opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes. Materials and MethodsAn observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded. ResultsThe whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present. ConclusionThe concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

Impact of CYP2D6 polymorphisms on adverse events in patients with breast cancer treated with tamoxifen: Insights from an early dose escalation trial in CYP2D6 poor metabolizers.

547 Background: Tamoxifen is widely used in treating hormone receptor-positive breast cancer. It is primarily metabolized by the CYP2D6 enzyme to yield active metabolites. However, CYP2D6 polymorphisms have been associated with a differential response to tamoxifen. In a clinical trial involving an early dose escalation of tamoxifen in poor metabolizers, we found endoxifen concentration levels similar to those of patients with extensive phenotype, and no long-term survival differences among CYP2D6 phenotypes. However, the impact of that dose escalation on side effect incidence was not addressed. Methods: In this study, we analyzed the incidence of specific side effects - osteoarticular pain, hot flashes, asthenia, and uterine alterations - in 86 breast cancer patients, differentiated by their CYP2D6 phenotype estimated according to the Clinical Pharmacogenetics Implementation Consortium. In poor metabolizers, the tamoxifen standard dose of 20 mg/day was escalated to 40 mg/day and 60 mg/day for 4 months each, and then treated with 20 mg/day until completing the treatment. Kaplan-Meier analysis and Cox proportional hazards regression model were employed to assess the relationship between the CYP2D6 phenotype and the incidence of these side effects. Results: The median follow-up time was 139.5 months. The analyses revealed that only uterine changes showed significant differences between CYP2D6 phenotypes, with a lower incidence in extensive metabolizers (P-value &lt; 0.001 in Kaplan-Meier; HR in Cox of 0.195, 95% CI 0.073 - 0.521, P = 0.001). This finding persisted after adjustment for the covariates tumor grade, size, nodal status, chemotherapy, and radiotherapy in multivariate Cox regression (HR 0.098, 95% CI 0.020 - 0.466, P = 0.004). Selection of a subgroup through Propensity Score Matching (21 vs 21) corroborated these results. The spectrum of uterine changes and pathologies included endometrial hyperplasia, polyps, adenocarcinoma, myometrial or endometrial thickening, and the presence of multiple myomas. Conclusions: Our study indicates that an early increase in tamoxifen dose in poor metabolizer patients according to CYP2D6 polymorphisms may significantly affect the incidence of uterine changes, but not the incidence of osteoarticular pain, hot flashes, or asthenia. Clinical trial information: 2007-002942-40/ES .

Pharmacogenomic insights in psychiatric care: uncovering novel actionability, allele-specific CYP2D6 copy number variation, and phenoconversion in 15,000 patients

Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.

Physiologically based pharmacokinetic modeling to predict the pharmacokinetics of codeine in different CYP2D6 phenotypes.

Codeine, a prodrug used as an opioid agonist, is metabolized to the active product morphine by CYP2D6. This study aimed to establish physiologically based pharmacokinetic (PBPK) models of codeine and morphine and explore the influence of CYP2D6 genetic polymorphisms on the pharmacokinetics of codeine and morphine. An initial PBPK modeling of codeine in healthy adults was established using PK-Sim® software and subsequently extrapolated to CYP2D6 phenotype-related PBPK modeling based on the turnover frequency (Kcat) of CYP2D6 for different phenotype populations (UM, EM, IM, and PM). The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between the predicted and observed values of the pharmacokinetic parameters to evaluate the accuracy of PBPK modeling. The validated models were then used to support dose safety for different CYP2D6 phenotypes. The developed and validated CYP2D6 phenotype-related PBPK model successfully predicted codeine and morphine dispositions in different CYP2D6 phenotypes. Compared with EMs, the predicted AUC0-∞ value of morphine was 98.6% lower in PMs, 60.84% lower in IMs, and 73.43% higher in UMs. Morphine plasma exposure in IMs administered 80mg of codeine was roughly comparable to that in EMs administered 30mg of codeine. CYP2D6 UMs may start dose titration to achieve an optimal individual regimen and avoid a single dose of over 20mg. Codeine should not be used in PMs for pain relief, considering its insufficient efficacy. PBPK modeling can be applied to explore the dosing safety of codeine and can be helpful in predicting the effect of CYP2D6 genetic polymorphisms on drug-drug interactions (DDIs) with codeine in the future.

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.

Phenotypes of CYP2D6 do not predict adverse events in patients with depression

Phenotypes of CYP2D6 do not predict adverse events in patients with depression

Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China.

The aim of this study was to investigate the frequency distribution of the cytochrome P450 (CYP450) enzymes, CYP2D6 and CYP2C19, and the form of tamoxifen metabolisation in premenopausal patients with breast cancer in the Han and Uygur ethnic groups of Xinjiang to guide rational clinical drug use. A total of 125 Han patients and 121 Uygur patients with premenopausal hormone-receptor-positive breast cancer treated at the Xinjiang Uygur Autonomous Region Cancer Hospital between 1 June 2011 and 1 December 2013 were selected. The common mutation sites in CYP450 were analysed using TaqMan® minor groove binder technology. Genetic testing was performed to determine other metabolic types of tamoxifen, and the genotypes and metabolic types were compared using a Chi-squared test. Between the Han and Uygur groups, there were significant differences in the frequencies of the CYP2D6 (*10/*10) and CYP2C19 (*1/*1) genotypes, with P-values of 0.002 and 0.015, respectively. Genotypes of CYP2D6 (*1/*1), CYP2D6 (*1/*5), CYP2D6 (*5/*5), CYP2D6 (*5/*10) and CYP2C19 (*3/*3) were expressed in the two patient groups, and the difference was not statistically significant (P > 0.05). In the Han patients, the proportions of extensive, intermediate and poor metabolisers of tamoxifen were 72, 24 and 4%, respectively, whereas those in the Uygur patients were 76.9, 17.4 and 5.7%, respectively, with no significant difference (P > 0.05). In conclusion, There were partial differences in the CYP2D6 and CYP2C19 gene polymorphisms of CYP450 between the Han and Uygur patients with premenopausal breast cancer, but there was no significant difference between the CYP2D6 and CYP2C19 phenotypes. Further research is needed to determine the relationship between the enzyme genetic differences of CYP450 and the pharmacokinetics and efficacy of tamoxifen. Although there were some differences in genotypes, these did not result in differences in the predicted tamoxifen metabolisation phenotype between the Han and Uygur patients with breast cancer. Therefore, the doses should be adjusted according to the individual genotype data.

Frequencies of CYP2C19 and CYP2D6 gene variants in a German inpatient sample with mood and anxiety disorders

Objectives Previous results demonstrated that CYP2D6 and CYP2C19 gene variants affect serum concentrations of antidepressants. We implemented a PGx service determining gene variants in CYP2D6 and CYP2C19 in our clinical routine care and report on our first patient cohort. Methods We analysed CYP2D6 and CYP2C19 allele, genotype, and phenotype frequencies, and actionable pharmacogenetic variants in this German psychiatric inpatient cohort. Two-tailed z-test was used to investigate for differences in CYP2D6 and CYP2C19 phenotypes and actionable/non-actionable genetic variant frequencies between our cohort and reference cohorts. Results Out of the 154 patients included, 44.8% of patients were classified as CYP2D6 normal metabolizer, 38.3% as intermediate metabolizers, 8.4% as poor metabolizers, and 2.6% as ultrarapid metabolizers. As for CYP2C19, 40.9% of patients were classified as normal metabolizers, 19.5% as intermediate metabolizers, 2.6% as poor metabolizers, 31.2% as rapid metabolizers, and 5.8% as ultrarapid metabolizers. Approximately, 80% of patients had at least one actionable PGx variant. Conclusion There is a high prevalence of actionable PGx variants in psychiatric inpatients which may affect treatment response. Physicians should refer to PGx-informed dosing guidelines in carriers of these variants. Pre-emptive PGx testing in general may facilitate precision medicine also for other drugs metabolised by CYP2D6 and/or CYP2C19.

Pharmacogenomic study-A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention.

To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed. Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status. We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Solanidine is a sensitive and specific dietary biomarker for CYP2D6 activity

BackgroundIndividual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes.ResultsUsing non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10–11), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10–4), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, − 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision–recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios.ConclusionsThese results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug–drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping.