Genetic Polymorphisms Of CYP2D6 Research Articles

Optimization of maintenance therapy of Risperidone with CYP2D6 genetic polymorphisms through an extended translational framework-based prediction of target occupancies/clinical outcomes.

Risperidone, one of the second-generation antipsychotics, can efficiently target dopamine D2 and serotonin 5-HT2A receptors. There actually exists significant implication of CYP2D6 genetic polymorphisms on the metabolic kinetics of risperidone, little is known about the extent of CYP2D6 impacting human D2 and 5-HT2A receptor occupancies as well as the clinical efficacy and efficacy in schizophrenia treatment. Here we assessed the influences of CYP2D6 gene polymorphisms on human target occupancies/clinical outcomes and optimized the maintenance therapy of risperidone. A translational framework, previously developed using in vitro and in vivo information in rats, was used as the basis for integrating the effects of CYP2D6 genetic polymorphisms on target occupancies and clinical outcomes. D2 occupancy as a biomarker was related to Positive and Negative Syndrome Scale (PANSS) response and Simpson-Angus Scale (SAS). The population approach was applied to characterize pharmacokinetic and pharmacodynamic (PK/PD) profiles of risperidone. Non-compartment analysis method was performed to calculate the steady state PK/PD parameters of both risperidone and 9-hydroxyrisperidone. The predictive power of this extended translational framework was determined by comparing the predictions of target occupancies and clinical outcomes with the reported human values of risperidone at clinically suggested dosage of 4.0 mg/day. This extended translational framework was adequately used to predict human target occupancies and clinical outcomes. At the steady state, D2 ROs were 75.8%, 79.3% and 86.0% for CYP2D6 poor metabolizer (PM), intermediate metabolizer (IM) and extensive metabolizer (EM), respectively; 5-HT2A ROs were 96.4%, 97.2% and 98.4% for CYP2D6 PM, IM and EM, respectively; PANSS changes from placebo were -5.3, -7.7 and -11.3 for CYP2D6 PM, IM and EM, respectively; SAS changes from placebo were 0.13, 0.15 and 0.18 for CYP2D6 PM, IM and EM, respectively. The predictions of human D2, 5-HT2A RO, PANSS and SAS changes for risperidone with CYP2D6 genetic polymorphisms were well in line with the reported values in clinic. 5.0, 4.0 and 2.5 mg/day were the equivalent dosages of risperidone for CYP2D6 PM, IM and EM, respectively. The optimized maintenance therapy of risperidone was provided through the Three-Step method and the dosage range was 2.5-5.0 mg/day for three CYP2D6 gene groups in the present study. Taken together, our findings demonstrate that this extended translational framework not only differentiates the effects of CYP2D6 genetic polymorphisms on target occupancies and clinical outcomes, but also constitutes a scientific basis to optimize the maintenance therapy of neuropsychiatric patients in clinic.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

IMPACT OF CYP3A5, CYP2C9, CYP2C19, AND CYP2D6 POLYMORPHISMS ON PHENAZEPAM SAFETY IN PATIENTS WITH ALCOHOL WITHDRAWAL SYNDROME

Introduction: Phenazepam is the Russian original benzodiazepine tranquilizer. We conducted first pharmacogenetic study on Phenazepam’s safety in patients with alcohol withdrawal syndrome. Isoenzymes CYP3A4, CYP3A5, CYP2C9, and CYP2C19 are involved into benzodiazepine tranquilizers’ metabolism.Aim: To determine predictive value of CYP3A5, CYP2C9, CYP2C19, and CYP2D6 genetic polymorphisms and their haplotypes for adverse reaction risk associated with the treatment with phenazepam.Materials and methods: The study enrolled 102 male patients with non-comlicated alcohol withdrawal syndrome (F10.3 by ICD-10) who entered the study group in 24 hours after the admission to hospital and was administered Phenazepam for 6 days. Therapy safety was evaluated with UKU Side Effects Rating Scale on the 6th day of treatment. 5 ml of venous blood was collected from each participant for genotyping to detect CYP3A5*3, CYP2С9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, and CYP2D6*4 polymorphisms by real-time polymerase chain reaction. Haplotype analysis was performed by SNPStats online-tool. Statistical analysis was made in SPSS Statistics 21.0.Results: In overall sample (n=102) CYP2C9*3 increased risk of «Increased duration of sleep» (OR 1.46; 95% CI 1.11−1.9; p=0.037) and «Constipation» (OR 13.1; 95% CI 1.44−119.2; p=0.02). The following results in subgroup «Phenazepam’s monotherapy» (n=64) were observed: CYP3A5*3 increased global severity of adverse drug reactions according to patient’s opinion (OR 2.79; 95% CI 1.26−6.22; p=0.031); CYP2C9*3 led to «Increased duration of sleep» (OR 1.57; 95% CI 1.14−2.17; p=0.034). Haplotype CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) was associated with increased risk of «Concentration difficulties (OR 2.86; 95% CI 0.96−8.50; p=0.061).Conclusion: The study findings confirmed that CYP2C9*3, CYP3A5*3, and CYP2C19*2 polymorphisms can decrease the phenazepam safety rate in patients with alcohol withdrawal syndrome. The result of haplotype analysis revealed that only CYP3A5*3-CYP2C19*2-CYP2C19*17 (G-G-T) can be used as a significant predictor of adverse reaction to phenazepam.

Abstract 1808: The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice

Abstract Endoxifen, the predominant CYP2D6 metabolite of the selective estrogen receptor modulator (SERM) tamoxifen, is currently being developed as a novel anti-estrogen therapy for the treatment of estrogen receptor (ER)+ breast cancer. Genetic polymorphism of CYP2D6 is a predictor of response to tamoxifen in patients, implicating endoxifen as one of the most active and relevant tamoxifen metabolites. Breast cancer patients treated with adjuvant endocrine therapies including aromatase inhibitors (AIs) and SERMs often report unmanageable musculoskeletal toxicities that can result in treatment discontinuation. While ER binding affinity and anti-tumor effects have been established in preclinical models, the effects of endoxifen on the musculoskeletal system are not fully known. Twenty-week female C57BL/6 mice underwent sham surgery or ovariectomy (OVX) and were treated daily with vehicle, the AI letrozole, or the SERM endoxifen. Body composition was assessed prospectively by DXA. Bone indices and marrow adipose tissue volume were measured by μCT and muscle contractility of the extensor digitorum longus (EDL) was measured ex vivo. After eight weeks, trabecular bone volume fraction (BV/TV) decreased by 50% in OVX-vehicle and OVX-letrozole mice, whereas BV/TV increased threefold in endoxifen mice relative to sham-vehicle. Despite the presence of significantly more trabecular bone following endoxifen treatment, cortical bone analyses revealed impaired periosteal and endosteal expansion of bone, resulting in reduced polar moment of inertia, which is a measure of resistance to fracture. Uterine weight increased significantly in endoxifen-treated mice relative to all OVX groups, similar to what is observed with tamoxifen treatment. Peripheral body fat, bone marrow adipose tissue, and circulating leptin were reduced by endoxifen, suggesting that the drug may elicit positive systemic metabolic effects. At the termination of the study, muscle-specific force was reduced in OVX-endoxifen mice relative to sham-vehicle, OVX-vehicle, and OVX-AI mice, despite no change in muscle mass. While endoxifen shows promise as a potent anti-estrogen therapy for the treatment of ER+ breast cancer, it may be important to monitor patients for endometrial proliferation, morphological changes in bone that increase fracture risk, and for musculoskeletal side effects that could reduce drug compliance. Citation Format: Laura Wright, Khalid Mohammad, Theresa Guise. The anti-estrogen endoxifen altered bone morphology and reduced muscle function in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1808.

Effects of CYP2D6 and CYP3A5 genetic polymorphisms on steady-state pharmacokinetics and hemodynamic effects of tamsulosin in humans.

Tamsulosin is one of the most potent drugs currently available to treat benign prostatic hyperplasia. Cytochrome P450 (CYP) 2D6 and CYP3A are the two major enzymes responsible for tamsulosin metabolism. The purpose of this study was to evaluate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on the pharmacokinetics and hemodynamic effects of tamsulosin in humans. Twenty-nine male subjects were enrolled and their CYP2D6 (*2,*4,*5,*10,*14,*21,*41, and *xN) and CYP3A5 (*5) genotypes were screened. Tamsulosin was administered daily for 6days to assess its steady-state pharmacokinetics and hemodynamic effects according to CYP2D6 and CYP3A5 genotypes. CYP2D6 group 3 (with genotype *10/*10 or *5/*10) exhibited higher plasma levels than CYP2D6 group 1 (with genotype *1/*1,*1/*2,*1/*2xN, or *2/*10xN) or CYP2D6 group 2 (with genotype *1/*10,*1/*41, or *2/*5) (trough concentrations for groups 1, 2, and 3: 1.3, 1.8, and 3.8ng/mL, respectively [P < 0.001]; peak concentrations for groups 1, 2, 3: 8.3, 10.0, and 13.8ng/mL, respectively [P < 0.005]). Similarly, CYP2D6 genotypes influenced the hemodynamic effects of tamsulosin based on systolic and diastolic blood pressures. However, the CYP3A5*3 polymorphism did not affect tamsulosin plasma levels and its hemodynamic effects. The CYP2D6 but not the CYP3A5 genetic polymorphisms affected the pharmacokinetics and the hemodynamic effects of tamsulosin.

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

BackgroundFluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis.ObjectiveThe primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance.MethodsThe study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction.ResultsAccording to results of Mann–Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day).ConclusionThis study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

CYP2D6 genotyping in the daily routine of a psychiatric hospital – pharmacoeconomic evaluation

Today, pharmacogenetic tests are commonly used to improve the efficacy and safety of antipsychotic (AP) treatment. However, the economic aspects of their implementation in the psychiatry clinic routine are not well studied. Aim. To evaluate the pharmacoeconomic benefits of CYP2D6 polymorphisms genotyping in psychiatric patients. Materials and methods. CYP2D6 genetic polymorphisms (*3, *4, *5, *6, *1ХN) were tested in 298 psychiatric in-patients. The mean AP daily doses and the hospital stay duration differed between poor (PM), extensive (EM) and ulta-rapid (UM) metabolizers. Based on these data, a pharmacoeconomic decision-making model was created. The model calculates direct medical costs for the patient care with and without pharmacogenetics tests. Results. Pharmacogenetics tests (CYP2D6 genotyping) performed prior to the antipsychotic therapy were shown to be a cost-effective strategy as it gives additional clinical and pharmacological information, optimize the duration of AP treatment, and results in a lower direct medical cost of in-patient care. The cost of genotyping is less than 1% of the total direct medical costs. This strategy remains cost-effective even if the genotyping costs more than 3893.8 RUB (199% of the current value) and also if the differences in the hospital stay durations between PM, EM and UM are not less than 5 days.

A randomized phase II trial evaluating CYP2D6 genotype-guided tamoxifen dosing in hormone receptor-positive metastatic breast cancer: TARGET-1.

1046Background: Tamoxifen (TAM) is a prodrug that requires metabolic activation by CYP2D6. Genetic polymorphism of CYP2D6 has been speculated to cause suboptimal efficacy of TAM. Methods: In a phas...

Phase I trial of z-endoxifen with estrogen receptor imaging in adults with advanced hormone receptor–positive solid tumors including desmoid and gynecologic tumors.

2516Background: Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphism...

Maternal Exposure to Pesticides, Paternal Occupation in the Army/Police Force, and CYP2D6*4 Polymorphism in the Etiology of Childhood Acute Leukemia.

Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1.87; 95% confidence intervals [CI], 1.04-3.33), with subjects living <100 m from pesticide-treated fields (OR=3.21; 95% CI, 1.37-7.53) and with a paternal occupation as traffic warden/policeman (OR=4.02; 95% CI, 1.63-9.87). Associations were found between CAL and genetic polymorphism of CYP2D6*4 for homozygous alleles (mutant type/mutant type: OR=6.39; 95% CI, 1.17-34.66). In conclusion, despite the small sample size, maternal prenatal exposure to pesticides, paternal occupation as a traffic warden/police officer, and CYP2D6*4 polymorphism could play a role in the etiology of CAL.

Effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in different CYP2D6 genotypes.

Tamsulosin, a selective antagonist of the α1-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2mg oral dose of tamsulosin. After a washout period of 1week, on day 8, the subjects were given a 60mg oral dose of diltiazem three times daily for four days. On day 10, 1h after the morning dose of diltiazem, they received a single 0.2mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the Cmax and AUCinf of tamsulosin in each CYP2D6 genotype group were significantly increased (p < 0.0001 for all). The CL/F of tamsulosin was also significantly decreased after diltiazem treatment (both p < 0.0001). However, diltiazem did not affect the t1/2 of tamsulosin in each genotype group. In conclusion, diltiazem significantly increases exposure to tamsulosin regardless of the genotype of CYP2D6. Dose adjustment in the daily maintenance dose of tamsulosin may improve tolerability and safety in patients receiving diltiazem.

P.1.003 - Pharmacodynamics and pharmacokinetics related gene polymorphisms affect adverse drug reactions of haloperidol

The antipsychotic action of haloperidol is due to the blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptors blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-Methyltransferase, glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) [1,2], and also genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate as well as plasma drug concentration ratio is described in patients with different genotypes [3,4]. To evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol use disorder who received haloperidol. The second objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. The study included 114 male patients (average age 38.12±9.08; median age 39; LQ 34; UQ 48). Bio-Rad CFX Manager™ software (USA) and "SNP-Screen" sets of "Syntol" (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826, and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with high-performance liquid chromatography-mass spectrometry using concentration of endogenous substrate of the enzyme and its urinary metabolites (6-hydroxy-1,2,3,4-tetrahydro-beta-carboline(6-HO-THBC) to pinoline ratio [5] for CYP2D6 and 6-beta-hydroxycortisol to cortisol ratio for CYP3A). The equilibrium plasma concentration was determined using LC-MS-MS. Statistical analysis of the results was performed with non-parametric methods using the ”Statsoft Statistica v. 10.0“ (Dell Statistica, Tulsa, OK, USA). The normality of samples distribution was evaluated using W-Shapiro-Wilk test and taken into account when choosing a method. The differences were considered as statistically significant at р<0.05 (power in excess of 80 %). To compare two independent groups Mann-Whitney U test was used. Results of this study detected a statistically significant difference in the adverse drug reactions intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets the increases in the UKU score of 10.99 ± 2.12 (10/10) vs 13.14 ± 2.08 (9/10) (p<0.001) and in the SAS score of 5.17 ± 1.49 (10/10) vs 6.88 ± 1.37 (9/10) (p=0.006) were revealed. The results of this study showed that equilibrium concentration level / dose index depends on CYP2D6 genetic polymorphism (0.19 [0.07; 0.43] vs 0.48 [0.38; 0.55], p=0.012). Polymorphism of the SCL6A3 gene can affect the safety of haloperidol, and that should be taken into account during the choice of drug and its dosage regimen. Also our study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Genetic polymorphism of CYP2D6*41 in different ethnicities of Iranian population

Genetic polymorphism of CYP2D6*41 in different ethnicities of Iranian population

Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites.

Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n=8; *wt=*1 or *2), CYP2D6*wt/*10 (n=8) and CYP2D6*10/*10 (n=6). Concentrations of clomiphene and its metabolites were determined using a validated HPLC-MS/MS analytical method in plasma samples collected up to 168h after the drug intake. There was a significant difference only in the Cmax of clomiphene between three CYP2D6 genotype groups (p<0.05). Paradoxically, the elimination half-life (t1/2) and AUC of both active metabolites were all significantly increased in the CYP2D6*10 homozygous carriers, compared with other genotype groups (all p<0.001). The AUCinf of corrected clomiphene active moiety in CYP2D6*10/*10 subjects was 2.95- and 2.05-fold higher than that of CYP2D6*wt/*wt and *wt/*10 genotype groups, respectively (both p<0.001). Along with the partial impacts on the biotransformation of clomiphene and its metabolites by CYP2D6 genetic polymorphism, further studies on the effects of other CYP enzymes in a multiple-dosing condition can provide more definite evidence for the inter-individual variabilities in clomiphene pharmacokinetics and/or drug response.

Abstract P3-12-03: Impact of genetic polymorphisms on plasma levels of tamoxifen and its metabolites and toxicity: 6-months results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295)

Abstract Supported by a PHRC grant (#09-18-005) Background: The role of CYP2D6 genetic polymorphisms and plasma levels of active metabolites of tamoxifen (TAM) on clinical response and occurrence of side effects remains controversial. We conducted a prospective, adjuvant, multicentre, 3-year follow-up study of breast cancer patients in order to evaluate the relationships between pharmacogenetics, pharmacokinetics and toxicity of TAM and its metabolites (n=879) or aromatase inhibitors (AI, n=1098). The present report focuses on the evaluation at 6 months after inclusion of 864 patients treated with 20 mg/day TAM.The clinical results and the AI PG/PK analyses are described elsewhere (abstracts #851544 and #851525). Methods: Residual plasma concentrations for tamoxifen and its 6 major metabolites (endoxifen ENDO, 4-hydroxy-tamoxifen 4-OH-TAM, N-desmethyl TAM, TAM-N-oxyde, 4'-OH-TAM and Z'ENDO) at 6 months after start of treatment were measured by UPLC-MS/MS in 789 patients. Nine patients with TAM concentrations below the limit of quantification were excluded for non-compliance. SNP genotyping of 95 selected SNPs was performed on the Biomark (Fluidigm) in a microfluidic multiplex 96 dynamic array chip with Taqman assays and was available for 857 patients. Patients were classified according to their CYP2D6 metaboliser status (MS) (PM, IM, EM and UM) based on presence of functional, decreased function or no functional alleles (*4, *6, *7, *9, *10, *17, *41) and number of CYP2D6 copies (*5 or duplication). Metabolic ratios (MR) were calculated for TAM/4-OH-TAM, TAM/N-desmethyl tamoxifen (NDT), NDT/ENDO and 4-OH-TAM/ENDO. Anti-estrogenic activity score (AAS) was calculated according to a recently proposed algorithm (De Vries Schultink et al.,Breast Cancer Res Treat. 2017).Toxicity was measured as a binary outcome (first occurrence or worsening of hot flushes, fatigue, depression, pain, arthralgia, vaginal dryness). All genetic associations were adjusted for multiple testing. Results: ENDO concentration and AAS increased significantly with CYP2D6 MS (p&amp;lt;0.001). The presence of a CYP3A4*22 allele was significantly associated with endoxifen concentrations; this association remained significant after adjusting for CYP2D6 MS. TAM/4-OH-TAM MR was significantly influenced by the presence of CYP3A4*22, CYP2C19*2 and *17, and CYP2D6 status. The percentage of patients having an AAS&amp;gt;=1798 (i.e., threshold previously associated with recurrence-free survival RFS by De Vries et al. 2017) was 6%, 50%, 84% and 91% of patients respectively classified as PM, IM, EM and UM. Side effects were not significantly associated with higher levels of TAM metabolites concentrations. After correction for multiple testing, SNPs or CYP2D6 MS were not significantly associated with occurrence or worsening of adverse events, premature treatment discontinuations or switch due to toxicity within the first 6 months. Conclusions: In this large prospective study, we quantified the impact of PG on TAM PK and AAS, previously shown to predict RFS. Although the toxicity observed after 6 months of TAM does not seem correlated with PK or PG, these relationships need to be re-evaluated during the 3-year follow-up. Citation Format: White-Koning M, Arellano C, Le Morvan V, Evrard A, Puzskiel A, Vachoux C, Dauba J, Houyau P, Poublanc M, Robert J, Boyer J-C, Roché H, Thomas F, Chatelut E. Impact of genetic polymorphisms on plasma levels of tamoxifen and its metabolites and toxicity: 6-months results of the adjuvant breast cancer longitudinal PHACS study (NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-03.

CYP2D6 Protein Level Is the Major Contributor to Interindividual Variability in CYP2D6-Mediated Drug Metabolism in Healthy Human Liver Tissue.

CYP2D6 genetic polymorphisms are considered a major contributor to the large interindividual variability in CYP2D6-mediated drug metabolism, but fail to explain a significant portion of the variability. The aim of this study was to assess the ability of the CYP2D6 activity score (AS) estimated from CYP2D6 genotype to predict CYP2D6 expression and enzyme activity. The CYP2D6 gene region was sequenced in 115 healthy human liver tissue samples to determine their CYP2D6 AS. Additionally, CYP2D6 enzyme activity, protein, and mRNA levels were estimated. CYP2D6 AS explained 23% of the interindividual variability in CYP2D6 activity, but only 7.5% in tissues assigned AS 1-2. The CYP2D6 protein level was found to be the major determinant of CYP2D6 activity, explaining 59% of variability. These findings suggest that while CYP2D6 AS is a good predictor of poor metabolizer phenotype, additional nongenetic factors may govern the rate of CYP2D6-mediated metabolism in those without the poor metabolizer phenotype.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data.

CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of a CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study was designed to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli. Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods. A total of 72 single nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population. The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in the Orang Asli of Peninsular Malaysia.

Should a routine genotyping of CYP2D6 and CYP2C19 genetic polymorphisms be recommended to predict venlafaxine efficacy in depressed patients treated in psychiatric settings?

The antidepressant venlafaxine (VEN) is metabolized by CYP2D6 and CYP2C19. The aim of this study was to assess the relevance of generalizing to daily practice the genotyping of CYP2D6 and CYP2C19 to predict VEN efficacy in depressed patients treated in psychiatric settings. This study was nested in a naturalistic cohort, with 206 patients requiring a new antidepressant treatment and genotyped for CYP2D6 *3, *4, *5 del, *6, *2xN, *10, *41 and CYP2C19 *2, *3, *4, *5, *17 alleles. CYP2D6 and CYP2C19 phenotypes were associated neither with the Hamilton depression rating scale score improvement, nor with response and remission. Routine CYP2D6 and CYP2C19 genotyping cannot be recommended to predict VEN efficacy in depressed patients treated in psychiatry settings.

CYP450 enzymes genetic polymorphism influence on treatment of affective disorders

IntroductionIndividualized treatment decisions in psychiatry may be important, since substantial part of first choice drugs are ineffective or cause side effects. Polymorphic variants of genes that code CYP450 enzymes cause differences in their activity and therefore in efficacy and safety of drugs that are metabolized by them.Aim of the studyDetermine whether pharmacogenetic testing of CYP2D6, CYP2C19 and CYP2C9 polymorphism would have had influence on selected patients’ treatment courses.MethodsFive patients that were diagnosed for treament-resistant mood disorders in Vilnius university hospital Santariskiu clinics centre of neurology, department of psychiatry were invited to give blood samples for genetic testing retrospectively. Patients’ CYP2C19, CYP2D6 and CYP2C9 enzymes genetic polymorphism results were compared with previous empirical pharmacological treatment courses of these patients.ResultsIn four out of five cases significant polymorphism of CYP2C19 enzyme allele was detected. In all of these cases 1*/2* variant, that conditions intermediate metabolizer phenotype, was identified. Alterations in CYP2D6 and CYP2C19 regions were not found. In three cases the presence of varied genetic variant could have been clinically relevant. In two of these cases Sertraline and valproates, that are both metabolized by CYP2C19 enzyme, were taken by patients and side effects were observed. Unsuccessful treatment was repeated without effect, both in clinical and outpatient environment. Continuous rehospitalization took place until appropriate empirical treatments were established.ConclusionsPharmacogenetic testing could have had influence on treatment choices for three out of five selected patients leading to less side effects and rehospitalizations.Disclosure of interestThe authors have not supplied their declaration of competing interest.