The role of polymorphic cytochrome P450 gene (CYP2B6) in B-chronic lymphocytic leukemia (B-CLL) incidence and outcome among Egyptian patients.

Cytochromes P450 (CYPs) play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75% of the total metabolism of commercially available drugs, including chemotherapeutics. The gene expression and enzyme activity of CYPs are variable between individuals, which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics, as well as differences in the efficacy and toxicity of clinically used drugs. This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients, as well as the clinical outcome after receiving cyclophosphamide chemotherapy. DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex- and age-matched healthy individuals. The presence of the CYP2B6*9 (G516T) polymorphism was examined by PCR-based allele specific amplification (ASA). Patients were further indicated for receiving chemotherapy, and then they were followed up. The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models, comprising allelic (T-allele vs. G-allele, OR = 4.8, p < 0.001) and dominant (GT + TT vs. GG, OR = 5.4, p < 0.001) models. Following cyclophosphamide chemotherapy, we found that the patients with variant genotypes (GT + TT) were less likely to achieve remission compared to those with the wild-type genotype (GG), with a response percentage of (37.5% vs. 83%, respectively). In conclusion, our findings showed that the CYP2B6*9 (G516T) polymorphism is associated with B-CLL susceptibility among Egyptian patients. This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.

Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability.

Cytochrome P450 mediated substrate metabolism is generally characterized by the formation of reactive intermediates. In vitro and in vivo reaction uncoupling, results in the accumulation and dissociation of reactive intermediates, leading to increased ROS formation. The susceptibility towards uncoupling and altered metabolic activity is partly modulated by pharmacogenomic alleles resulting in amino acid substitutions. A large variability in the prevalence of these alleles has been demonstrated in CYP2B6, with some being predominantly unique to African populations. The aim of this study is to characterize the uncoupling potential of recombinant CYP2B6*1, CYP2B6*6 and CYP2B6*34 metabolism of specific substrates. Therefore, functional effects of these alterations on enzyme activity were determined by quantification of bupropion, efavirenz and ketamine biotransformation using HPLC-MS/MS. Determination of H2O2 levels was performed by the AmplexRed/horseradish peroxidase assay. Our studies of the amino acid substitutions Q172H, K262R and R487S revealed an exclusive use of the peroxide shunt for the metabolism of bupropion and ketamine by CYP2B6*K262R. Ketamine was also identified as a trigger for the peroxide shunt in CYP2B6*1 and all variants. Concurrently, ketamine acted as an uncoupler for all enzymes. We further showed that the expressed CYP2B6*34 allele results in the highest H2O2 formation. We therefore conclude that the reaction uncoupling and peroxide shunt are directly linked and can be substrate specifically induced with K262R carriers being most likely to use the peroxide shunt and R487S carrier being most prone to reaction uncoupling. This elucidates the functional diversity of pharmacogenomics in drug metabolism and safety.

Single-nucleotide polymorphism in CYP1A1, CYP1B1, CYP2B6, CYP2C8, and CYP2C9 genes and their association with gastrointestinal cancer: A hospital-based case-control study.

BACKGROUND: Cytochrome P450 (CYP) comprises a group of phase-I metabolizing enzymes that are important in xenobiotics metabolism. Genetic polymorphism of CYPs has been comprehensively studied for their association with a range of diseases. In this study, we assessed single-nucleotide polymorphism (SNP) of CYP1A, CYP1B, CYP2B, and CYP2C and their role in gastrointestinal (GI) cancer susceptibility in the rural population of Maharashtra. MATERIALS AND METHODS: In this hospital-based case-control study, the association of polymorphism of CYP genes was studied by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study subjects included 200 clinically confirmed GI cancer patients and equal number of healthy controls. Odds ratio (OR) with 95% confidence interval (CI) and P value were evaluated to find out the level of association, where P ≤ 0.005 was considered statistically significant. RESULTS: After the analysis of CYP1A1*2A (rs4646903), CYP1B1*3 (rs1059836), CYP2B6*5 (rs3211371), CYP2C8*2 (rs11572103), CYP2C9*2 (rs1799853), and CYP2C9*3 (rs1057910), we noticed that variant (T) allele of CYP2B6*5 possessed significantly elevated risk (OR = 4.43; 95% CI: 2.20-8.90; P < 0.0001) of GI cancer in studied population. The genotypic distribution of G/C heterozygote allele of CYP1B1*3 (OR = 0.19, 95% CI = 0.12-0.32; P < 0.0001) and homozygous variant C/C allele (OR = 0.24, 95% CI = 0.13-0.45; P < 0.0001) showed a negative association with the development of GI cancer. CONCLUSION: The findings from this study supported that polymorphism of CYP2B6*5gene may be involved in the development of GI cancer. However, other SNPs of CYP1A, CYP1B, and CYP2C genes did not signify the risk for GI cancer in the studied population of rural Maharashtra.

Brain-derived neurotrophic factor Val66Met and CYP2B6 polymorphisms as predictors for ketamine effectiveness in patients with treatment-resistant depression.

BACKGROUND: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response. AIMS: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine. METHODS: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine. RESULTS: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation. CONCLUSIONS: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P  < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

Characterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations.

Genetic variation in CYP2B6 and CYP2A6 is known to impact interindividual response to antiretrovirals, nicotine, and bupropion, among other drugs. However, the full catalogue of clinically relevant pharmacogenetic variants in these genes is yet to be established, especially across African populations. This study therefore aimed to characterize the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy, and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n = 2,000). This study presents frequency information for star alleles in CYP2B6 (e.g., *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g., *4, *9, and *17; frequency of 0-6%, 3-10%, and 6-20%, respectively), and predicted phenotypes (for CYP2B6), across various African populations. In addition, 50 potentially novel African-ancestry star alleles were computationally predicted by StellarPGx in CYP2B6 and CYP2A6 combined. For each of these genes, over 4% of the study participants had predicted novel star alleles. Three novel star alleles in CYP2A6 (*54, *55, and *56) and CYP2B6 apiece, and several suballeles were further validated via targeted Single-Molecule Real-Time resequencing. Our findings are important for informing the design of comprehensive pharmacogenetic testing platforms, and are highly relevant for personalized medicine strategies, especially relating to antiretroviral medication and smoking cessation treatment in Africa and the African diaspora. More broadly, this study highlights the importance of sampling diverse African ethnolinguistic groups for accurate characterization of the pharmacogene variation landscape across the continent.

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

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized ß 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 ß 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.

Methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical implications.

BACKGROUND: A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. OBJECTIVES: We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings. METHODS: We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. FINDINGS: A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. CONCLUSIONS: This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes.

Genetic polymorphisms of CYP2B6 is a risk of metabolic associated fatty liver disease in Chinese population.

BACKGROUND: The expression and activity of cytochrome P450 2B6 (CYP2B6) may be related to the metabolic associated fat liver disease (MAFLD). Since constitutive androstane receptor (CAR) is a classic transcriptional regulator of CYP2B6, and the single nucleotide polymorphisms (SNPs) of CYP2B6 and CAR are both associated with adverse reactions of efavirenz, we hypothesized that genetic polymorphisms of CAR might also result in additional interindividual variability in CYP2B6. This study was devoted to explore the association between CYP2B6 and CAR SNPs and susceptibility to MAFLD. MATERIALS AND METHODS: A total of 590 objects of study (118 with MAFLD and 472 healthy control) between December 2014 and April 2018 were retrospectively enrolled. Twenty-two selected SNPs in CYP2B6 and CAR were genotyped with a custom-designed 48-plex SNP Scan TM® Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between the two groups. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS: The T allele of rs3745274 in CYP2B6 was associated with a decreased risk for MAFLD (OR 0.610; 95% CI: 0.451-0.825, p = 0.001) which was still statistically significant after adjusting with Bonferroni method(p = 0.014) The allele, genotype and genetic model frequencies were similar in the two groups for the other twenty-one SNPs (all P > 0.05). There were no multiplicative or additive interactions between the SNPs. CONCLUSION: Our study revealed that rs3745274 variants in CYP2B6 is associated with susceptibility to MAFLD in the Han Chinese population.

Association of CYP3A5*3, CYP3A4*18 & CYP2B6*6 polymorphisms with imatinib treatment outcome in Azerbaijani chronic myeloid leukaemia patients.

Background & objectives: Imatinib mesylate (IM) is a reliable first line treatment for chronic myeloid leukaemia (CML). Nevertheless, despite promising results, a considerable proportion of patients develop resistance to the drug. Cytochrome P450 (CYP) enzymes play a crucial role in IM metabolism. Thus, point mutations in CYP genes may modify IM enzyme activity resulting in insufficient treatment response. This investigation was aimed to identify the functional impact of CYP3A5*3, CYP3A4*18 and CYP2B6*6 polymorphisms on the IM response in patients with CML in Azerbaijan. Methods: Genotyping of CYP3A5*3, CYP3A4*18 and CYP2B6*6 was performed in 153 patients (102 IM non-responders and 51 IM responders) with CML by the PCR-restriction fragment length polymorphism (RFLP) assays. The odds ratios (ORs) with 95 per cent confidence intervals (CIs) were applied to assess the association between allelic variants and IM therapy outcome. The results were validated by sequencing. Results: The frequency of the CYP3A4*18 allele was considerably lower in the responder's group (97.1 vs. 100%; P=0.036). For CYP3A5*3, the allelic frequency was slightly higher among the IM responders (100 vs. 99.02%) with no significant difference. Although patients heterozygous (TC) for CYP2B6*6 demonstrated a higher risk of acquiring resistance (OR 1.04; 95% CI: 0.492-2.218), differences were not significant (P=0.909). In addition, the homozygous genotype (TT) demonstrated a lower risk of unresponsiveness (OR 0.72; 95% CI: 0.283-1.836), but associations were not significant (P=0.491). Interpretation & conclusions: Our results demonstrated that CYP3A4*18 was significantly associated with IM treatment response in patients with CML in Azerbaijan, whereas rather common CYP3A5*3 was identified to have no such association.

Genetic polymorphisms effect on cyclophosphamide's tolerability and clinical efficacy in Egyptian patients with lupus nephritis.

OBJECTIVES: Many studies were conducted to determine the association between genetic polymorphisms in CYP2B6 c.516G>T and cyclophosphamide (CYC) efficacy or toxicity, no studies were focused on both clinical efficacy and toxicity of CYC. This study aimed to investigate the relationship between the CYP2B6 c.516G>T polymorphism (rs 3745274) and 17 different parameters related to CYC efficacy and tolerability in Egyptian patients with lupus nephritis (LN). METHODS: A prospective cohort study on 142 LN patients with a mean age of 36.26 was conducted at Kasr Al Ainy School of Medicine, Cairo University, Egypt after the exclusion of 14 patients due to receiving an interacting medication with CYC. All clinical parameters related to CYC efficacy or toxicity were recorded and compared between the different genotypes. RESULTS: There was a statistically significant difference between different genotypes in 11 out of 13 of the studied efficacy-related parameters. Many of the studied clinical parameters revealed that CYC's efficacy was associated with the presence of the T allele. There was a statistically significant difference between different genotypes in hepatotoxicity, diarrhea, and blood-related toxicities. CONCLUSION: To our knowledge, this study is the first study that focused on studying 17 different parameters related to CYC efficacy and tolerability. Our findings paint a picture of the function that CYP2B6 polymorphisms play in Egyptian LN patients. Pre-treatment evaluation of CYP2B6 rs 3745274 may account for some individual differences in treatment response.

Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma.

Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00979589.

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

OBJECTIVE: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. METHODS: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. RESULTS: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CONCLUSION: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

BACKGROUND: The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. METHODS: In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. RESULTS: Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. CONCLUSION: We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

Physiologically Based Pharmacokinetic Modeling to Determine the Impact of CYP2B6 Genotype on Efavirenz Exposure in Children, Mothers and Breastfeeding Infants.

The antiretroviral drug efavirenz remains widely used in children and mothers during breastfeeding in tuberculosis-endemic areas. Evaluating the safety of efavirenz during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk, its exposure in the breastfed infant, and the potential influence of polymorphisms in drug disposition genes. The interplay of these factors between the mother and the nursing infant is a complex scenario that can be readily investigated using physiologically-based PK (PBPK) modeling. A verified PBPK model for efavirenz describing the CYP3A4- and CYP2B6-mediated auto-induction during multiple dosing was reported previously and was applied in this study to predict the exposure of efavirenz in vulnerable populations, including children (down to the age of 3 months), mothers, and breastfeeding infants, accounting for the various CYP2B6 genotypes. Predicted pharmacokinetic parameters for mothers, breastfeeding infants, and children aged ≥ 3 months were reasonably consistent with observed data, irrespective of CYP2B6 genotype. The clinically significant trend toward higher infant efavirenz exposure from GG/GG to TT/TT composite maternal/infant CYP2B6 genotypes was captured reasonably well by the PBPK model. Thereafter, simulations were performed to determine the adequacy of the current World Health Organization (WHO; ≥ 3 years) and the US Food and Drug Administration (FDA; ≥ 3 months) weight-based dosing regimens for efavirenz in children according to CYP2B6 genotype. The findings of this study indicate that PBPK models can be used in designing studies in vulnerable populations and providing guidance on optimal doses based on developmental physiology and pharmacogenetics.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

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.

Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study.

BACKGROUND: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum. METHODS: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.