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Aims: Methadone maintenance therapy (MMT) exhibits significant variability in pharmacokinetics and clinical response, partly due to genetic variations. However, data from sub‐Saharan African populations are lacking. We examined plasma methadone variability and pharmacogenetic influences among opioid‐addicted Tanzanian patients. Methods: Patients attending MMT clinics (n = 119) in Tanzania were genotyped for common functional variants of the CYP3A4, CYP3A5, CYP2A6, CYP2B6, CYP2C19, CYP2D6, ABCB1, UGT2B7 and SLCO1B1 genotypes. Trough plasma concentrations of total methadone, S‐methadone (S‐MTD) and R‐methadone (R‐MTD), with their respective metabolites, 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP), were quantified using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The methadone‐to‐EDDP metabolic ratio (MMR) was used to categorize the phenotype. Results: The proportions of MMR‐predicted ultrarapid, extensive, intermediate and slow methadone metabolizer phenotypes were 2.5%, 58.2%, 23.7% and 15.6%, respectively. CYP2B6 genotype significantly correlated with S‐methadone (P =.006), total methadone (P =.03), and dose‐normalized methadone plasma concentrations (P =.001). Metabolic ratios of R‐methadone (R‐MTD/R‐EDDP), S‐methadone (S‐MTD/S‐EDDP), and total methadone (MMR) were significantly higher among patients homozygous for defective variants (*6 or *18) than heterozygous or CYP2B6*1/*1 genotypes (P <.001). The metabolic ratio for S‐MTD and total methadone was significantly higher among ABCB1c.3435T/T than in the C/C genotype. No significant effect of CYP2D6, CYP2C19, CYP3A4, CYP3A5, CYP2A6, UGT2B7 and SLCO1B1 genotypes on S‐methadone, R‐methadone, or total methadone was observed. Conclusions: Approximately one in six opioid‐addicted Tanzanian patients are methadone slow metabolizers, influenced by genetic factors. Both the CYP2B6 and ABCB1 genotypes are strong predictors of methadone metabolic capacity and plasma exposure. Further investigation is needed to determine their predictive value for methadone treatment outcomes and to develop genotype‐based dosing algorithms for safe and effective therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain.Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O‐desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference.The pharmacokinetics of tramadol and M1 was characterized by a two‐compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6‐mediated metabolism (CLPM) and other pathways (CLPO). Age‐related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM,  and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady‐state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively.In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2D6 (CYP2D6) is a key enzyme that mediates the metabolism of various drugs and endogenous substances in humans. However, its biological role in drug‐drug interactions especially mechanism‐based inactivation (MBI), and various diseases remains poorly understood, owing to the lack of molecular tools suitable for selectively monitoring CYP2D6 in complex biological systems. Herein, using a tailored molecular strategy, we developed a fluorescent probe BDPM for CYP2D6. BDPM exhibits excellent specificity and imaging capability for CYP2D6, making it suitable for the real‐time monitoring of endogenous CYP2D6 activity in living bio‐samples. Therefore, our tailored strategy proved useful for constructing the highly selective and enzyme‐activated fluorescent probes. BDPM as a molecular tool to explore the critical roles of CYP2D6 in the pathogenesis of diseases, high‐throughput screening of inhibitors and intensive investigation of CYP2D6‐induced MBI in natural systems. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real‐world population. Methods: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N‐desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype‐predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration‐to‐dose (CD) ratio and metabolite‐to‐parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal–Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. Results: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P <.001), 28% in CYP2C19 IMs (P <.001) and 31% in CYP2C19 PMs (P =.04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. Conclusions: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone. [ABSTRACT FROM AUTHOR]

Beta‐blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta‐blocker exposure and response. We searched and summarized the strength of the evidence linking beta‐blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta‐blockers or for any beta‐blocker and the other five genes evaluated (updates at www.cpicpgx.org). [ABSTRACT FROM AUTHOR]

The ability of freely available in silico tools to predict the effect of non‐synonymous single nucleotide polymorphisms (nsSNPs) in pharmacogenes on protein function is not well defined. We assessed the performance of seven sequence‐based (SIFT, PolyPhen2, mutation accessor, FATHMM, PhD‐SNP, MutPred2, and SNPs & Go) and five structure‐based (mCSM, SDM, DDGun, CupSat, and MAESTROweb) tools in predicting the impact of 118 nsSNPs in the CYP2C19, CYP2C9, CYP2B6, CYP2D6, and DPYD genes with known function (24 normal, one increased, 42 decreased, and 51 no‐function). Sequence‐based tools had a higher median (IQR) positive predictive value (89% [89–94%] vs. 12% [10–15%], P < 0.001) and lower negative predictive value (30% [24–34%] vs. 90% [80–93%], P < 0.001) than structure‐based tools. Accuracy did not significantly differ between sequence‐based (59% [37–67%]) and structure‐based (34% [23–44%]) tools (P = 0.070). Notably, the no‐function CYP2C9*3 allele and decreased function CYP2C9*8 allele were predicted incorrectly as tolerated by 100% of sequenced‐based tools and as stabilizing by 60% and 20% of structure‐based tools, respectively. As a case study, we performed mutational analysis for the CYP2C9*1, *3 (I359L), and *8 (R150H) proteins through molecular dynamic (MD) simulations using S‐warfarin as the substrate. The I359L variant increased the distance of the major metabolic site of S‐warfarin to the oxy‐ferryl center of CYP2C9, and I359L and R150H caused shifts in the conformation of S‐warfarin to a position less favorable for metabolism. These data suggest that MD simulations may better capture the impact of nsSNPs in pharmacogenes than other tools. [ABSTRACT FROM AUTHOR]

Hydrocodone, tramadol, codeine, and oxycodone are commonly prescribed opioids that rely on activation by cytochrome P450 2D6 (CYP2D6). CYP2D6 inhibitors can significantly decrease CYP2D6 activity, leading to reduced generation of active metabolites, and impairing pain control. To understand this impact, we assessed emergency department (ED) visits in patients initiating these CYP2D6‐dependent opioids while on CYP2D6‐inhibitor antidepressants vs. antidepressants that do not inhibit CYP2D6. This retrospective cohort study included adult patients prescribed CYP2D6‐dependent opioids utilizing electronic health records data from the University of Florida Health (2015–2021). The association between ED visits and inhibitor exposure was tested using multivariable logistic regression. The primary analysis had 12,118 patients (72% female; mean (SD) age, 55 (13.4)) in the hydrocodone/tramadol/codeine cohort and 5,547 patients (64% female; mean (SD) age, 53.6 (14.2)) in the oxycodone cohort. Hydrocodone/tramadol/codeine‐treated patients exposed to CYP2D6‐inhibitor antidepressants (n = 7,043) had a higher crude rate of pain‐related ED visits than those taking other antidepressants (n = 5,075) (3.28% vs. 1.87%), with an adjusted odds ratio (aOR) of 1.75 (95% CI: 1.36 to 2.24). Similarly, in the oxycodone cohort, CYP2D6‐inhibitor antidepressant‐exposed individuals (n = 3,206) had a higher crude rate of ED visits than individuals exposed to other antidepressants (n = 2,341) (5.02% vs. 3.37%), with aOR of 1.70 (95% CI: 1.27–2.27). Similar findings were observed in secondary and sensitivity analyses. Our findings suggest patients with concomitant use of hydrocodone/tramadol/codeine or oxycodone and CYP2D6 inhibitors have more frequent ED visits for pain, which may be due to inadequate pain control. [ABSTRACT FROM AUTHOR]

Tamoxifen is widely used in patients with hormone receptor‐positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z‐endoxifen. The Z‐endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z‐endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z‐endoxifen concentration and tamoxifen treatment outcomes, and identify a Z‐endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed‐effect (NLME) model for tamoxifen and Z‐endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z‐endoxifen. The final parent‐metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co‐medication with CYP2D6 inhibitors, on Z‐endoxifen pharmacokinetics. Future work will use the model to simulate Z‐endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long‐term survival to identify the Z‐endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor‐positive breast cancer. [ABSTRACT FROM AUTHOR]

Atogepant, an oral calcitonin gene‐related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P‐glycoprotein (P‐gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P‐gp and CYP2D6 inhibitor. A phase 1 open‐label study evaluated the effect of P‐gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co‐administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co‐administration. The overall systemic exposure, the area under the plasma concentration‐time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co‐administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment‐emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1‐2 days. Co‐administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co‐administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P‐gp. [ABSTRACT FROM AUTHOR]

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6‐guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT‐PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6‐impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6‐guided trial recommendations. The primary study outcome is the 3‐month absolute change in the composite pain intensity score assessed using Patient‐Reported Outcomes Measurement Information System (PROMIS) measures. Follow‐up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA‐MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6‐specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account. [ABSTRACT FROM AUTHOR]

The Department of Veterans Affairs (VA) utilizes a pharmacogenomic (PGx) program that analyzes specific "pharmacogenes." This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co‐primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabolizers for CYP3A5. Patients were classified as having 0, 1, and 2+ total phenotypes across all genes. Of the 15,144 patients screened, 13,116 met eligibility criteria. Across phenotype cohorts, there was no significant association with polypharmacy using all medications, number of total medications, or number of medications affected by phenotypes. However, there was a significant difference in patients with polypharmacy prescribed ≥1 medication impacted by PGx across phenotype groups: 2,514/4,949 (51%), 1,349/2,595 (52%), 204/350 (58%) (P = 0.03, OR 1.31, 95% CI 1.02–1.67). The median number of medications affected by PGx phenotypes with ≥1 PGx‐impacted medication across phenotype groups was a median of 0 (IQR 0, 0), 0 (IQR 0, 0), and 1 (IQR 0, 1) (P < 0.001). In patients prescribed ≥1 medication impacted by PGx, those with more actionable pharmacogenomic phenotypes were more likely to meet polypharmacy criteria. [ABSTRACT FROM AUTHOR]

Although great progress has been made in the fine‐tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug‐metabolizing enzymes. [ABSTRACT FROM AUTHOR]

Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30–100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome‐wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early‐stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse‐free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome‐wide significance (P value: ≤5 × 10−8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2–21.1; rs6790761, OR 18.2, 95% CI: 15.5–21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene. [ABSTRACT FROM AUTHOR]

This document summarizes a pilot study conducted in Denmark to assess the agreement between publicly funded genotyping tests and phenotype classification for certain genes. The study found inconsistencies in genotype and phenotype agreement between three laboratories, highlighting the need for standardization in pharmacogenetic testing. The document also discusses the lack of national alignment between laboratories in Denmark, which poses challenges in the use and implementation of pharmacogenetic testing. The study recommends continuous updating of the phenotype approach and alignment of genotyping and phenotyping classifications to ensure consistent implementation of pharmacogenetic testing in Denmark. The document also references various guidelines and studies related to pharmacogenetic testing in mental health care settings. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Aims: Previously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne. Methods: Thirty‐three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual‐probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre‐isotretinoin treatment and with isotretinoin for at least 1 week. The concentrations of isotretinoin, DM and their metabolites were measured in 2‐h postdose plasma samples and in cumulative 0‐4‐h urine collections using liquid chromatography‐mass spectrometry. Results: In CYP2D6 extensive metabolizers, the urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly, lower with isotretinoin administration compared to pre‐isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)] 0.78 [0.55, 1.11]). The urinary 3‐hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR 1.18 [1.03, 1.35]) and the urinary DX‐O‐glucuronide/DX MR (proposed UGT2B marker) was increased (GMR 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre‐isotretinoin. Conclusions: Administration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest that DX glucuronidation is increased following isotretinoin administration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Genetic variants affect drug responses, making pre‐emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre‐emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population‐level benefits of pre‐emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene‐drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high‐risk phenotypes. We collected reported risk reduction from genotyping and standardized it into population attributable risks. Healthcare reimbursement costs for SAEs and treatment failures were obtained from the Health Insurance Review and Assessment Service Statistics in 2021. The benefits of pre‐emptive genotyping for a specific group were determined by multiplying drug exposure from nationwide cohort data by individual genotyping benefits. We identified 31 gene‐drug‐event pairs, with CYP2D6 and CYP2C19 demonstrating the greatest benefits for both male and female patients. Individuals aged 65–70 years had the highest individual benefit from pre‐emptive genotyping, with $84.40 for men and $100.90 for women. Pre‐emptive genotyping, particularly for CYP2D6 and CYP2C19, can provide substantial benefits. [ABSTRACT FROM AUTHOR]

Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug–drug interactions (DDIs). Real‐world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation. Scoring was based on prevalence of exposure to victim substrates and characteristics (age, polypharmacy, duration of exposure, and number of prescribers) of those exposed. The study population of 14,163,271 adults included 1,579,054 with T2DM, 3,117,753 with obesity, and 410,436 with migraine. For T2DM, 71.3% used CYP3A substrates, 44.3% used CYP2D6 substrates, and 44.3% used CYP2C9 substrates. For obesity, 57.1% used CYP3A substrates, 34.6% used CYP2D6 substrates, and 31.0% used CYP2C9 substrates. For migraine, 64.1% used CYP3A substrates, 44.0% used CYP2D6 substrates, and 28.9% used CYP2C9 substrates. In our analyses, the predicted DDI impact scores were highest for DDIs involving CYP3A, followed by CYP2D6, and CYP2C9 substrates, and highest for T2DM, followed by migraine, and obesity. Insights from RWD can be used to estimate a predicted DDI impact score for pharmacokinetic DDIs perpetrated by new drug candidates currently in development. This score can inform the risk/benefit profile of new drug candidates in a target patient population. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%–25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6‐mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra‐high performance liquid chromatography‐high‐resolution mass spectrometry in a cohort of 463 CYP2D6‐genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83‐ and 3.38‐fold higher M416‐to‐solanidine (p = 0.039) and M444‐to‐solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6‐mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans. [ABSTRACT FROM AUTHOR]

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary‐derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4‐OH‐solanidine and 3,4‐secosolanidine‐3,4‐dioic acid (SSDA) were determined using a sensitive liquid chromatography‐mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra‐individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α‐OH‐metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day. [ABSTRACT FROM AUTHOR]

Background: Amitriptyline (AT) is recommended as first‐line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice. Methods: This pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well‐characterized cohort of adults with CVS. Key Results: Of 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra‐rapid metabolizers. There was no statistically significant association between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result. Conclusions and Inferences: A subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bersiporocin, a potent and selective prolyl‐tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open‐label, two‐part, one‐sequence, three‐period, three‐treatment study was designed to evaluate the effect of drug–drug interactions (DDI) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated, enteric‐coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses, and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose of nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. Forty‐six participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs, suggesting bersiporocin alone or in combination therapy were well‐tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there are no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib. [ABSTRACT FROM AUTHOR]

Introduction: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer‐related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6‐guided opioid prescribing for patients with cancer and reported pilot outcome data. Methods: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation‐effectiveness clinical trial and randomized to CYP2D6‐genotype‐guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient‐reported pain and symptom scores at baseline and up to 8 weeks, were assessed. Results: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3–37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6‐genotype‐guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow‐up questionnaires (n = 48), there was no difference in change in mean composite pain score (−1.01 ± 2.1 vs. −0.41 ± 2.5; p = 0.19) or symptom severity at last follow‐up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype‐guided arm (n = 22), respectively. Conclusion: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype‐guided recommendations was low, impacting assessment of pain‐related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success. [ABSTRACT FROM AUTHOR]

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus and a comprehensive summary of structural variation. CYP2D6 contributes to the metabolism of numerous drugs and, thus, genetic variation in its gene impacts drug efficacy and safety. To accurately predict a patient's CYP2D6 phenotype, testing must include structural variants including gene deletions, duplications, hybrid genes, and combinations thereof. This tutorial offers a comprehensive overview of CYP2D6 structural variation, terms, and definitions, a review of methods suitable for their detection and characterization, and practical examples to address the lack of standards to describe CYP2D6 structural variants or any other pharmacogene. This PharmVar tutorial offers practical guidance on how to detect the many, often complex, structural variants, as well as recommends terms and definitions for clinical and research reporting. Uniform reporting is not only essential for electronic health record‐keeping but also for accurate translation of a patient's genotype into phenotype which is typically utilized to guide drug therapy. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most used hormonal therapy for oestrogen receptor‐positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC‐MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N‐desmethyl‐tamoxifen ratios (P = 0.0006). [ABSTRACT FROM AUTHOR]

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β‐adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross‐sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self‐described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p =.0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p =.0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions. [ABSTRACT FROM AUTHOR]

Understanding cannabis‐drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ‐9‐tetrahydrocannabinol (Δ9‐THC), the most abundant phytocannabinoids, are in vitro reversible and time‐dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid‐drug interactions in 18 healthy adults. Participant received, in a randomized cross‐over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD‐dominant cannabis extract (640 mg CBD + 20 mg Δ9‐THC), or (iii) Δ9‐THC‐dominant cannabis extract (20 mg Δ9‐THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0–24 hours). The CBD + Δ9‐THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration‐time curve (AUC) relative to placebo (AUCGMR) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9‐THC brownie did not inhibit any of the CYPs. The CBD + Δ9‐THC brownie increased Δ9‐THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9‐mediated oral Δ9‐THC clearance. Except for caffeine, these interactions were well‐predicted by our physiologically‐based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co‐consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9‐THC. [ABSTRACT FROM AUTHOR]

Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty‐six paraffin tumor samples from ASCC patients were analyzed by whole‐exome sequencing. Copy number variants (CNVs) were identified and their relation to disease‐free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty‐nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p <.0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7–24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p =.02, HR = 3.6; 95% CI, 1.1–5.7). Mitochondria and mitochondrial cell‐cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5‐fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell‐cycle genes as possible therapeutic targets for these high‐risk patients. Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s.However, disease‐free survival in late staged tumors is between 40% and 70%.The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease‐free survival.The analysis of the proteins in these high‐risk patients pointed out mitochondria and mitochondrial cell‐cycle genes as possible therapeutic targets.Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high‐risk of relapse that could be redirected to a clinical trial.Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy. The presence of a copy number variant in CYP2D6 gene in localized anal squamous cell carcinoma tumors is a biomarker of worse disease‐free survival. Proteomics pointed out mitochondria and mitochondrial cell‐cycle genes as possible targets for these high‐risk patients. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2D6 (CYP2D6) is an important drug‐metabolizing enzyme exhibiting extensive interindividual variability predominantly caused by genetic polymorphism. Predicting CYP2D6 function based on genotype may be used to personalize pharmacotherapy, but the process of translating CYP2D6 genotype into predicted phenotype is complex and has suffered from a lack of consensus. The Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group have proposed a standardized translation scheme based on the activity score system aiming to facilitate more consistent CYP2D6 genotype–phenotype translation. However, this system remains suboptimal particularly with regards to decreased function alleles and substrate‐specific behaviour. This review summarizes the process and challenges for functional assignment of CYP2D6 alleles. We discuss population pharmacokinetics (popPK) as a tool for estimating CYP2D6 function and present findings from three popPK meta‐analyses quantifying the impact of individual CYP2D6 alleles in the metabolism of vortioxetine, tedatioxetine and brexpiprazole. Findings from these analyses indicate that the activity values currently assigned to decreased function alleles CYP2D6*9, *17 and *41 overestimate their function. Moreover, the CYP2D6*2 allele exhibited reduced activity in the metabolism of brexpiprazole, indicating substrate‐specific behaviour. Considering the totality of the evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles. [ABSTRACT FROM AUTHOR]

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) and is therefore recommended for use in clinical drug–drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P‐gp, it is susceptible to DDIs involving these proteins. Physiologically‐based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug–drug(–gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P‐gp perpetrators as well as CYP2D6 and P‐gp victims. The quinidine parent‐metabolite model including 3‐hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1–600 mg). The model covers efflux transport via P‐gp and metabolic transformation to either 3‐hydroxyquinidine or unspecified metabolites via CYP3A4. The 3‐hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two‐fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two‐fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is. [ABSTRACT FROM AUTHOR]

Flucloxacillin is a widely used antibiotic. It is an agonist to the nuclear receptor PXR that regulates the expression of cytochrome P450 (CYP) enzymes. Treatment with flucloxacillin reduces warfarin efficacy and plasma concentrations of tacrolimus, voriconazole, and repaglinide. We conducted a translational study to investigate if flucloxacillin induces CYP enzymes. We also investigated if flucloxacillin induces its own metabolism as an autoinducer. We performed a randomized, unblinded, two‐period, cross‐over, clinical pharmacokinetic cocktail study. Twelve healthy adults completed the study. They ingested 1 g flucloxacillin 3 times daily for 31 days, and we assessed the full pharmacokinetics of the Basel cocktail drugs on days 0, 10, and 28, and plasma concentrations of flucloxacillin on days 0, 9, and 27. The 3D spheroid of primary human hepatocytes (PHHs) were exposed to flucloxacillin (concentration range: 0.15–250 μM) for 96 hours. Induction of mRNA expression, protein abundance, and enzyme activity of CYP enzymes were assessed. Flucloxacillin treatment reduced the metabolic ratio of midazolam (CYP3A4), (geometric mean ratio (GMR) 10 days (95% confidence interval (CI)): 0.75 (0.64–0.89)) and (GMR 28 days (95% CI): 0.72 (0.62–0.85)). Plasma concentrations of flucloxacillin did not change during 27 days of treatment. Flucloxacillin caused concentration‐dependent induction of CYP3A4 and CYP2B6 (mRNA, protein, and activity), CYP2C9 (mRNA and protein), CYP2C19 (mRNA and activity), and CYP2D6 (activity) in 3D spheroid PHH. In conclusion, flucloxacillin is a weak inducer of CYP3A4, which may lead to clinically relevant drug–drug interactions for some narrow therapeutic range drugs that are substrates of CYP3A4. [ABSTRACT FROM AUTHOR]

Aims: Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced‐function CYP2C19 genotype on atomoxetine concentrations in real‐world settings. Methods: Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced‐function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3‐*6, *9‐*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose‐adjusted serum atomoxetine concentration was the exposure measure. Results: Using a patient cohort (n = 315), it was found that CYP2D6 IM and PM patients had 1.9‐fold (95% confidence interval: 1.4–2.7) and 9.6‐fold (5.9–16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5‐fold (1.1–2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. Conclusion: CYP2D6 genotype has a great impact on atomoxetine exposure, where our real‐world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre‐emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects. [ABSTRACT FROM AUTHOR]

The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once‐daily administration for 15 days in a phase 1 multiple‐ascending‐dose study in healthy subjects. Probe substrates specific for the enzymes, i.e., caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4), were administered orally as a cocktail with (day 15) and without (day −3) enarodustat. Drug interaction was based on geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve from the time of dosing to infinity (AUCinf) ratios (day 15/day −3) for CYP1A2, 2C9, 2C19, 2D6, 3A4, and urinary excretion of dextromethorphan metabolite dextrorphan for CYP2D6. At the 2 enarodustat doses, for caffeine, the geometric mean ratios (range) for Cmax and AUCinf were 0.99–1.06 and 1.61–1.63, respectively. The ratios for peak concentrations and total exposures were 0.98–1.07 and 0.71–1.78 for tolbutamide and omeprazole, respectively. For dextrorphan the Cmax and AUCinf ratios were 0.83–0.90 and 1.02–1.04, respectively. The mean dextrorphan cumulative amount excreted into the urine from the time of dosing to 24 hours values on day −3 and day 15 were 8.25 mg and 8.20 mg at the lower dose, and 9.40 mg and 9.51 mg at the higher dose. The ratios for midazolam Cmax and AUCinf were 1.42–1.63. Overall, there was a lack of enarodustat dose dependency regarding the geometric mean ratios and 90% confidence intervals and urinary excretion of dextrorphan. There were some cases where the 90% confidence intervals at the 2 enarodustat doses were outside the 0.80–1.25 range, but changes in the geometric mean ratios were all <2‐fold. [ABSTRACT FROM AUTHOR]

Over 20% of US Food and Drug Administration (FDA)‐approved drugs in the United States are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6). The gene encoding CYP2D6 is highly polymorphic and genetic variation has been shown to impact drug response for many commonly dispensed drugs including opioids and antidepressants. Thus, it is important to understand an individual's CYP2D6 metabolizer status to optimize treatment outcomes for patients taking medications that are metabolized by this enzyme. Consequently, clinical CYP2D6 pharmacogenetic testing is being implemented by a growing number of health centers. Furthermore, clinical guidelines currently recommend adapting therapeutic regimens based on CYP2D6 genotype‐informed phenotype. However, CYP2D6 genetic variation varies considerably across global populations and many allelic variants, or star alleles, are predominantly found in certain ancestral populations. Although CYP2D6 genetic variation has been extensively studied, there is still a paucity of information for many non‐European populations. As has been shown for other pharmacogenes in randomized controlled trials, results from European populations cannot simply be extrapolated to other groups and, in some cases, even has the potential to cause harm. Therefore, enhanced inclusion in pharmacogenetic studies is urgently needed to increase ancestral representation, determine the extent of global CYP2D6 genetic variation (e.g., ancestry‐specific variants), and determine the clinical impact of this variation on clinical treatment outcome. This review highlights knowledge gaps, challenges, and future directions in CYP2D6 pharmacogenomics through a unique pharmacoequity lens to address health inequities that hamper our ability to optimize drug therapy for improved pharmacological outcomes in diverse populations globally. [ABSTRACT FROM AUTHOR]

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI‐like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin‐2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study (NCT04369391) evaluated the effects of ulotaront (SEP‐363856), a novel trace amine‐associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single‐dose, three‐period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by‐time‐point analysis (secondary analysis), the upper bound of the two‐sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration‐QTc analysis (primary analysis), a linear mixed‐effects model with ulotaront and its major metabolite SEP‐383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP‐383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady‐state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP‐383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose. [ABSTRACT FROM AUTHOR]

Aims: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for tardive dyskinesia treatment by the US Food and Drug Administration; its major active metabolite (NBI‐98782) is a 45‐fold more potent inhibitor of VMAT2 than the parent drug. This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability and the effect of cytochrome P450 2D6 (CYP2D6) genotypes to the PKs after the administration of valbenazine in Korean participants. A randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose study was conducted in healthy Korean male participants. The single‐dose study was conducted for both 40 and 80 mg valbenazine and the multiple dose study was conducted for 40 mg. After a 1‐week washout, the 40 mg dose group participants received valbenazine 40 mg or placebo once daily for 8 days. Serial blood samples were collected up to 96 h postdose for PK analysis. The CYP2D6 genotypes of the participants were retrospectively analyzed. A total of 50 participants were randomized, and 43 and 20 participants completed the single‐ and multiple‐dose phases of the study, respectively. After single doses, the PK characteristics of valbenazine and its metabolites were similar between the 40 and 80 mg dose groups. After multiple doses, the mean accumulation ratios of valbenazine and NBI‐98782 were ~1.6 and 2.4, respectively. Plasma concentrations of valbenazine and NBI‐98782 were similar between CYP2D6 normal and intermediate metabolizers. Valbenazine was well‐tolerated in healthy Koreans, and its PK characteristics were similar to results previously reported in Americans. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4‐hydroxy‐tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross‐ancestry genome‐wide association study with well‐characterized patients of European, Middle‐Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome‐wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1‐megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N‐desmethyltamoxifen (minimal P = 5.4E−35 and 2.5E−65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to −0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2) and 72% of the variability in endoxifen and MR endoxifen/N‐desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long‐distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2D6 (CYP2D6) is a key enzyme in drug response owing to its involvement in the metabolism of ~ 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic, and many pharmacogenetics studies have been performed worldwide to investigate the distribution of CYP2D6 star alleles (haplotypes); however, African populations have been relatively understudied to date. In this study, the distributions of CYP2D6 star alleles and predicted drug metabolizer phenotypes—derived from activity scores—were examined across multiple sub‐Saharan African populations based on bioinformatics analysis of 961 high‐depth whole genome sequences. This was followed by characterization of novel star alleles and suballeles in a subset of the participants via targeted high‐fidelity Single‐Molecule Real‐Time resequencing (Pacific Biosciences). This study revealed varying frequencies of known CYP2D6 alleles and predicted phenotypes across different African ethnolinguistic groups. Twenty‐seven novel CYP2D6 star alleles were predicted computationally and two of them were further validated. This study highlights the importance of studying variation in key pharmacogenes such as CYP2D6 in the African context to better understand population‐specific allele frequencies. This will aid in the development of better genotyping panels and star allele detection approaches with a view toward supporting effective implementation of precision medicine strategies in Africa and across the African diaspora. [ABSTRACT FROM AUTHOR]

Tea is a worldwide consumed herbal beverage and it was aimed in this study to reveal the major fractions of green and black tea in order to enlighten the in vitro inhibition potency on the well‐known drug metabolizing enzyme CYP2D6 activity. Methylxanthine fractions were extracted from green and black tea and a yield of 0.265 g (1.06%) for 25 g of dried black tea and 0.302 g (1.2%) for 25 g of green tea was calculated. High‐performance liquid chromatography analysis represented that the major components of the methylxanthine fractions were caffeine, theobromine, and theophylline. Methylxanthine content of black tea was 368.25 ± 4.6 μg/ml caffeine, 89.30 ± 2.3 μg/ml theobromine, and 3.40 ± 0.5 μg/ml theophylline, whereas that of green tea was 176.50 ± 3.7 μg/ml caffeine, 53.85 ± 1.4 μg/ml theobromine, and 2.06 ± 0.7 μg/ml theophylline. The results of concentration‐dependent inhibition studies were 76% green tea, 75% black tea, and 55% caffeine at concentration of 10 mg/ml. The inhibition rates of green and black tea on CYP2D6 activity were 76% and 75%, respectively, where that of quinidine, the well‐known inhibitor of CYP2D6, was 82%. Our results indicate that green and black tea is very likely to modify the CYP2D6 enzyme activity. [ABSTRACT FROM AUTHOR]

Scientific literature describes that sumatriptan is metabolized by oxidative deamination of its dimethylaminoethyl residue by monoamine oxidase A (MAO A) and not by cytochrome P450 (CYP)-mediated demethylation, as is usual for such structural elements. Using recombinant human enzymes and HPLC-MS analysis, we found that CYP enzymes may also be involved in the metabolism of sumatriptan. The CYP1A2, CYP2C19, and CYP2D6 isoforms converted this drug into N-desmethyl sumatriptan, which was further demethylated to N,N-didesmethyl sumatriptan by CYP1A2 and CYP2D6. Otherwise, sumatriptan and its two desmethyl metabolites were metabolized by recombinant MAO A but not by MAO B to the corresponding acetal- dehyde, with sumatriptan being only a poor substrate for MAO A compared to the N-demethylated and the N,N-didemethylated derivatives. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine whether CYP2D6 metabolizer status within the ondansetron‐treated pediatric tonsillectomy population is associated with risk of postoperative nausea and vomiting (PONV) in the post‐anesthesia care unit. We conducted a retrospective cohort study of pediatric patients (<18 years) who underwent tonsillectomy and received ondansetron on the day of the procedure. Data were obtained from BioVU, an institutional biobank that links DNA to de‐identified electronic health record data. Subjects were tested for 10 CYP2D6 allelic variants and copy number variation, and genotype data translated into CYP2D6 metabolizer status. The cohort included 652 individuals, 105 (16.1%) of whom had PONV. Rates of PONV were similar across groups: ultrarapid metabolizers (UMs), 1 of 9 (11.1%); normal metabolizers (NMs), 64 of 354 (18.1%); intermediate metabolizers (IMs), 33 of 234 (14.1%); poor metabolizers (PMs), 6 of 39 (15.4%); and ambiguous phenotypes, 1 of 16 (6.3%). In multivariable analysis adjusted for age, sex, and time under anesthesia, CYP2D6 metabolizer status was not associated with PONV, with an odds ratio of 1.37 (95% confidence interval 0.9, 2.1) when comparing PM/IM versus NM/UM. In this large pediatric population, no significant differences were detected for PONV based on CYP2D6 metabolizer status. Further investigation is needed to determine mechanisms for ondansetron inefficacy in children. [ABSTRACT FROM AUTHOR]

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype–phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM‐3411 and DM‐3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM‐3412, is formed via CYP2D6, the metabolic ratio of DM‐3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype–phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild‐type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate‐specific enzyme activity. [ABSTRACT FROM AUTHOR]