Ultrarapid Metabolizer Phenotype Research Articles

CYP2B6 and ABCB1 genotypes predict methadone plasma exposure among patients on maintenance therapy against opioid addictions in Tanzania.

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. 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. 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. 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.

Study protocol of the HD-MED study aiming to personalize drug treatment in Huntington's disease: a longitudinal, observational study to assess medication use and efficacy in relation to pharmacogenetics.

Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Currently, HD can only be managed symptomatically, including a large variety of prescribed drugs. Many HD patients experience negative medication effects (e.g. side effects or non-response). Pharmacogenetic (PGx) studies show how genetic variation affects both medication efficacy and toxicity and holds the potential to improve these outcomes of drug treatment. To classify the effect of the PGx profile of CYP2C19 and CYP2D6 in HD gene expansion carriers on negative medication effects of HD-related medication. Multicenter, observational study with 1-year follow-up. Adult HD gene expansion carriers who use one or more HD-related medications are eligible to participate. A detailed overview of medication use, medication efficacy, and side effects is retrospectively and prospectively collected via medication diaries, questionnaires, phone calls, and pharmacy medication verification schemes. PGx analysis on whole blood-extracted DNA is performed with Agena Bioscience VeriDose® Core Panel and long-range polymerase chain reaction copy number variation analysis. Per the study protocol-defined negative medication effects in HD gene expansion carriers with a genotype predicted poor or ultrarapid metabolizer phenotype will be compared with HD gene expansion carriers with a predicted intermediate and normal metabolizer phenotype. Frequencies will be analyzed via χ2 and logistic multivariate regression analysis. In addition, we summarize in this manuscript HD-relevant PGx prescription recommendations to improve drug therapy. The original study protocol was approved by the medical research ethics committee Leiden Den Haag Delft on 26 November 2019. HD-MED is a low-risk study that will generate personalized PGx results that can immediately be implemented in clinical practice, thus potentially improving pharmacovigilance and patients' quality of life. This study is registered in the International Clinical Trial Registry Platform under registration number NL8251, URL https://trialsearch.who.int/Trial2.aspx?TrialID=NL8251.

Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children

BackgroundThis study used therapeutic drug monitoring (TDM) and CYP2C19 gene polymorphism analysis to explore the efficacy and safety of different doses of voriconazole (VCZ) for the clinical treatment of pediatric patients, with the aim of providing guidelines for individualized antifungal therapy in children.MethodsOur study enrolled 94 children with 253 VCZ concentrations. The genotyping of CYP2C19 was performed by polymerase chain reaction (PCR)-pyrosequencing. VCZ trough concentration (Ctrough) was detected by high-performance liquid chromatography-tandem mass spectrometry. SPSS 23.0 was used to analyze the correlations between VCZ concentration, CYP2C19 phenotype, adverse effects (AEs), and drug-drug interactions.ResultsA total of 94 children aged between 1 and 18 years (median age 6 years) were enrolled in the study. In total, 42.6% of patients reached the therapeutic range at initial dosing, while the remaining patients reached the therapeutic range after the adjustment of the dose or dosing interval. CYP2C19 gene polymorphism was performed in 59 patients. Among these patients, 24 (40.7%) had the normal metabolizer (NM) phenotype, 26 (44.1%) had the intermediate metabolizer (IM) phenotype, and 9 (15.3%) had the poor metabolizer (PM) phenotype. No cases of the rapid metabolizer (RM) or ultrarapid metabolizer (UM) phenotypes were found. The initial VCZ Ctrough was significantly higher in patients with the PM and IM phenotypes than in those with the NM phenotype. The combination of immunosuppressive drugs (ISDs) did not affect VCZ Ctrough. The incidence of AEs was 25.5%, and liver function damage (46.2%) and gastrointestinal reactions (19.2%) were the most common.ConclusionsOur study showed significant individual differences of VCZ metabolism in children. Combining TDM with CYP2C19 gene polymorphism has important guiding significance for individualized antifungal therapy in pediatric patients.

Genotype-Guided Voriconazole Prescribing in Lung Transplant Recipients

<h3>Purpose</h3> Voriconazole (VRC) is the treatment of choice for Aspergillus in lung transplant recipients. VRC undergoes metabolism via CYP2C19, a polymorphic enzyme that has varying metabolic activity. Patients with either CYP2C19 ultrarapid metabolizer (URM) or rapid metabolizer (RM) phenotypes are less likely to achieve therapeutic VRC levels, which is predictive of treatment failure. Determining CYP2C19 variations can help tailor VRC therapy for lung transplant recipients. <h3>Methods</h3> This prospective cohort study included lung transplant recipients who received VRC between January 1, 2016, to November 30, 2019. Participants were excluded if they did not read or speak English, did not have access to email or internet, and did not provide consent to pharmacogenomic testing. The frequency of various CYP2C19 genotypes in this cohort was identified. <h3>Results</h3> Forty-three VRC exposures occurred in 34 participants who completed pharmacogenomic testing. Twenty-one percent (7/34) had URM or RM phenotypes, 74% (25/34) had normal (NM) or intermediate (IM) metabolizer phenotypes, and 6% (2/34) had poor metabolizer (PM) phenotype. Participants with URM or RM phenotypes required an average of 40 days to reach first therapeutic VRC levels, compared to 13 days and 9 days in the NM or IM and PM phenotypes, respectively. Eight cystic fibrosis participants were included in this cohort. Cystic fibrosis participants with URM or RM phenotypes required 77 days to reach first therapeutic VRC levels, while NM or IM and PM phenotypes required 27 days and 14 days, respectively. <h3>Conclusion</h3> The time required to achieve therapeutic VRC levels was widely variable based on CYP2C19 genotype and the corresponding phenotype in our study cohort. Participants with URM or RM phenotypes are at high risk for treatment failure due to prolonged time to therapeutic VRC levels. CYP2C19 polymorphism may further reduce likelihood of achieving target VRC levels in cystic fibrosis patients.

Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study

BackgroundMethadone use for the management of opioid dependency during pregnancy is commonplace. Methadone levels are altered during pregnancy due to changes in maternal physiology. Despite this, a paucity of data exist regarding the most appropriate optimal dosing regimens during pregnancy. MethodsThis study applied a pharmacokinetic modeling approach to examine gestational changes in R- and S-methadone concentrations in maternal plasma and fetal (cord) blood. This study did so to derive a theoretical optimal dosing regimen during pregnancy, and to identify the impact of Cytochromes P450 (CYP) 2B6 and 2C19 polymorphisms on methadone maternal and fetal pharmacokinetics. ResultsThe study noted significant decreases in maternal R- and S-methadone plasma concentrations during gestation, with concomitant increases in fetal levels. At a dose of 90 mg once daily, 75% (R-) and 94% (S-) of maternal methadone trough levels were below the lower therapeutic window at term (week 40). The developed optimal dosing regimen escalated doses to 110 mg by week 5, followed by 10 mg increments every 5 weeks up to a maximum of 180 mg once daily near term. This increase resulted in 27% (R-) and 11% (S-) of subjects with trough levels below the lower therapeutic window at term. CYP2B6 poor metabolizers (PM) and either CYP2C19 extensive metabolizers (EM), PM, or ultra-rapid (UM) metabolizer phenotypes demonstrated statistically significant increases in concentrations when compared to their matched CYP2B6 EM counterparts. ConclusionsSpecific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study.

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100-150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.

A hybrid implementation-effectiveness randomized trial of CYP2D6-guided postoperative pain management

Purpose:Cytochrome P450 2D6 (CYP2D6) genotype-guided opioid prescribing is limited. The purpose of this type 2 hybrid implementation-effectiveness trial was to evaluate the feasibility of clinically implementing CYP2D6-guided post-surgical pain management and determine that such an approach did not worsen pain control.Methods:Adults undergoing total joint arthroplasty were randomized 2:1 to genotype-guided or usual pain management. For participants in the genotype-guided arm with a CYP2D6 poor (PM), intermediate (IM), or ultra-rapid metabolizer (UM) phenotype, recommendations were to avoid hydrocodone, tramadol, codeine, and oxycodone. The primary endpoints were feasibility metrics and opioid use; pain intensity was a secondary endpoint. Effectiveness outcomes were collected 2-weeks post-surgery.Results:Of 282 patients approached, 260 (92%) agreed to participate. In the genotype-guided arm, 20% had a high-risk (IM/PM/UM) phenotype, of whom 72% received an alternative opioid versus 0% of usual care participants (p<0.001). In an exploratory analysis, there was less opioid consumption (200 [104-280] vs. 230 [133-350] morphine milligram equivalents; p=0.047) and similar pain intensity (2.6 ± 0.8 vs. 2.5 ± 0.7; p=0.638) in the genotype-guided vs. usual care arm, respectively.Conclusion:Implementing CYP2D6 to guide post-operative pain management is feasible and may lead to lower opioid use without compromising pain control.

A review of the existing literature on buprenorphine pharmacogenomics.

Buprenorphine is an effective treatment for opioid dependence; however, it demonstrates individual variability in efficacy. Pharmacogenomics may explain this drug response variability and could allow for tailored therapy on an individual basis. The Food and Drug Administration and the Clinical Pharmacogenomics Implementation Consortium have guidelines on pharmacogenomic testing for some opioids (e.g., codeine); however, no guidelines exist for the partial opioid agonist buprenorphine. Pharmacogenomic testing targets for buprenorphine include pharmacodynamic genes like the mu-opioid receptor (MOP receptor) and catechol-O-methyltransferase (COMT), as well as the pharmacokinetic genes like the CYP enzymes. In this review we identified genotypes in patients with opioid addiction receiving buprenorphine that may result in altered therapeutic dosing and increased rate of relapse. The OPRM1 A118G single nucleotide polymorphism (SNP rs1799971) gene variant encoding the N40D MOP receptor has been associated with variable efficacy and response to treatment in both adult and neonatal patients receiving buprenorphine for treatment of opioid withdrawal. An SNP associated with rs678849 of OPRD1, coding for the delta opioid receptor, was associated with opioid relapse as indicated by opioid positive urine drug screens; there was also sex specific SNP identified at rs581111 and rs529520 in the European American population. COMT variability, particularly in rs4680, has been associated with length of stay and need for opioid treatment in patients with neonatal abstinence syndrome. Variations of the pharmacokinetic gene for CYP3A4 showed that the ultrarapid metabolizer phenotype required higher doses of buprenorphine. Genotyping of patients may allow us to appropriately tailor buprenorphine therapy to individual patients and lead to improved patient outcomes; however, further research on the pharmacogenomics of buprenorphine is needed.

Nonresponse to High-Dose Bupropion for Depression in a Patient Carrying CYP2B6 *6 and CYP2C19 *17 variants: a case report

We report the case of a patient with major depression treated with high-dose bupropion due to prior detected subtherapeutic blood concentrations at standard dosing. Pharmacogenetic panel testing identified the patient as a carrier of the CYP2B6*6 allele, which has been associated with reduced bupropion metabolism and decreased concentrations of the pharmacologically active metabolite hydroxybupropion. Interestingly, we also found the patient to be homozygous for the CYP2C19*17 allele, predicting an ultra rapid metabolizer phenotype. We propose a combined effect of the detected CYP2C19 and CYP2B6 genetic variants on bupropion metabolism. This case underlines the potential benefit of pre-emptive pharmacogenotyping but also the yet still fragmentary evidence making precise pharmacogenotype guided antidepressant selection and dosing challenging.

Histone Methyltransferase G9a Regulates Expression of Nuclear Receptors and Cytochrome P450 Enzymes in HepaRG Cells at Basal Level and in Fatty Acid Induced Steatosis.

Obesity and nonalcoholic fatty liver disease (NAFLD) affect expression and function of cytochrome P450 genes (P450s). The increased expression of inflammatory cytokines is a major driver of the downregulation of P450 expression in NAFLD. Decrease in P450 expression could potentially lead to drug-drug interaction, inefficient pharmacological effect of a drug, or hepatotoxicity. An epigenetic modifier, histone 3 lysine 9 methyl transferase enzyme (G9a), known to increase histone 3 lysine 9 methylation, is downregulated in diet-induced obesity animal models. In a liver-specific G9a knockout animal model, expression of P450s was downregulated. Currently, the role of G9a in regulation of P450s in steatosis is unknown. Our hypothesis is that in steatosis G9a plays a role in downregulation of P450 expression. In this study, we used HepaRG cells to induce steatosis using a combination of free fatty acids oleic acid and palmitic acid. The G9a was knocked down and overexpressed using small interfering RNA and adenovirus mediated approaches, respectively. Knockdown and overexpression of G9a in the absence of steatosis decreased and increased expression of nuclear receptors constitutive androstane receptor (CAR), pregnane X receptor, small heterodimer partner, and CYP2B6, 2E1, 2C8, 2C9, and 3A4, respectively. In steatotic conditions, overexpression of G9a prevented fatty acid mediated decreased expression of CAR, CYP2C19, 2C8, 7A1, and 3A4. Our current study suggests that G9a might serve as a key regulator of P450 expression at both the basal level and in early steatotic conditions. Single nucleotide polymorphism of G9a leading to loss/gain of function could lead to the poor metabolizer or ultrarapid metabolizer phenotypes. SIGNIFICANCE STATEMENT: The current study demonstrates that histone modification enzyme G9a is involved in the regulation of expression of nuclear receptors constitutive androstane receptor, pregnane X receptor, and small heterodimer partner as well as drug-metabolizing cytochrome P450s (P450s) at basal conditions and in fatty acid induced cellular model of steatosis. Histone 3 lysine 9 methylation should be considered together with histone 3 lysine 4 and histone 3 lysine 27 methylation as the epigenetic mechanisms controlling gene expression of P450s.

Clinical pharmacogenomic testing impacts therapy decisions and supportive medication choices in breast cancer.

569 Background: Pharmacogenomics, the study of the interaction between the patient’s genome and therapeutic drug response, evaluates the associations between efficacy and toxicity through analysis of drug metabolizing enzymes. As personalized medicine advances to the forefront of cancer care, pharmacogenomics can evaluate the individual’s ability to metabolize key medications in breast cancer treatment including anti-emetics, opioids, and tamoxifen. Women who do not achieve optimal levels of the active metabolites of tamoxifen are at higher risk of recurrence. Patients on chemotherapy who do not respond to anti-emetics can suffer from nausea and vomiting resulting in dehydration and hospitalization. This project evaluates the feasibility and therapeutic impact of real time pharmacogenomics in a selection of patients at the Inova Schar Cancer Institute (ISCI). Methods: An interdisciplinary team was created through the ISCI and the Inova Translational Medicine Institute to implement cheek swab based pharmacogenomic testing in 50 new patients undergoing mastectomy or neoadjuvant chemotherapy for breast cancer. Study patients were assessed for genotypic variability of key CYP enzymes and resulting impact on anti-emetic choices, perioperative pain control, and tamoxifen use. Results: Data was collected in a RedCap database. The 50 women enrolled were ages 28-83. Cheek swabs were performed in clinic and median turn around time was 7 days. 24 distinct genotypes were found in the 50 patients. 20% had abnormal CYP2D6 phenotypes indicating abnormalities in tamoxifen metabolism. 28% of patients had results leading to changes in dose or medication choice of perioperative pain control. 6% of patients had a CYP2D6 ultra-rapid metabolizer phenotype and were given granisetron in lieu of ondansetron. These patients had no documented nausea or vomiting requiring dose adjustments to the treatment plan or medical intervention. 40% of patients had results recommending avoidance of tamoxifen, 75% of which have ER+ breast cancer. 25% of patients had recommended changes to the dose of tamoxifen. Conclusions: Pharmacogenomic testing is feasible and available real-time for immediate use in the clinic. CYP mutations impact treatment decisions in a significant proportion of patients. Individualized treatment plans tailored to pharmacogenomic recommendations can be created in the multi-disciplinary setting and may decrease side effects of treatment and improve efficacy of curative therapy.

Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure.

The purpose of this study was to identify specific pharmacokinetic (PK) and pharmacodynamics (PD) factors that affect the likelihood of treatment remission with a serotonin norepinephrine reuptake inhibitor (SNRI) in depressed patients whose initial selective serotonin reuptake inhibitor (SSRI) failed. Multiple logistic regression modeling of PK and PD variation hypothesized to contribute to SNRI (i.e. duloxetine or venlafaxine) treatment remission in prior SSRI (i.e. citalopram or escitalopram) failure was conducted on 139 subjects from the Pharmacogenomics Research Network (PGRN) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies. Depressive symptoms were assessed with the Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C16). Venlafaxine-XR remission was associated with a significant interaction between CYP2D6 ultra-rapid metabolizer (URM) phenotype and SLC6A4 5-HTTLPR L/L genotype. A similar significant interaction effect was observed between CYP2D6 URM and SLC6A2 G1287A GA genotype. Stratifying by transporter genotypes, venlafaxine-XR remission was associated with CYP2D6 URM in patients with SLC6A4 L/L (p = 0.001) and SLC6A2 G1287A GA genotypes. The primary limitation of this post hoc study was small sample size. Our results suggest that CYP2D6 ultra-rapid metabolizer status contributes to venlafaxine-XR treatment remission in MDD patients; in particular, there is a PK-PD interaction with treatment remission associated with CYP2D6 URM phenotype and SLC6A4 5-HTTLPR L/L or SLC6A2 G1287A G/A genotype, respectively. These preliminary data are encouraging and support larger pharmacogenomics studies differentiating treatment response to mechanistically different antidepressants in addition to further PK-PD interactive analyses.

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.

Molecular Dynamics Simulations Reveal Structural Differences among Allelic Variants of Membrane-Anchored Cytochrome P450 2D6.

Cytochrome P450 2D6 (CYP2D6) is an enzyme that is involved in the metabolism of roughly 25% of all marketed drugs and therefore belongs to the most important enzymes in drug metabolism. CYP2D6 features a high degree of genetic polymorphism that can significantly affect the metabolic activity of an individual. In extreme cases, structural changes at the level of single amino acids can either increase its enzymatic activity abolishing the drug therapeutic effect or completely disable the enzyme and elevate drug plasma level potentially leading to adverse effects. In this study, starting from the crystal structure, we built a full-length membrane-anchored all-atom model of the wild-type CYP2D6 as well as five of its variants differing in the enzymatic activity. We validated our models with available experimental data and compared their structural properties with molecular dynamics simulations. The main focus of this study was to identify differences that could mechanistically explain the altered activity of the variants and improve our understanding of their functioning. We observed differences in the opening frequencies and minimal diameters of tunnels that connect the buried active site to the surrounding solvent environment. The variants CYP2D6*4 and CYP2D6*10 associated with missing or decreased activity showed less frequent opening of the tunnels compared to the wild-type. Both CYP2D6*10 and CYP2D6*17 showed a deprivation of an important ligand tunnel suggesting a feasible reason for their altered substrate specificity. Next, the altered fold at the N-terminal anchor region and the decreased active site volume caused by the amino acid mutations of the CYP2D6*4 variant offer an explanation for the absence of its metabolic activity. The mutations in CYP2D6*53 contributed to a significant enlargement of an important ligand tunnel and an extension of the active site cavity. This could explain the altered metabolic profile as well as the enhanced metabolic rates of this particular variant supporting its designation as a possible cause for the ultrarapid metabolizer phenotype. We believe these novel structural insights could advance the fields of personalized medicine and enzyme engineering. Furthermore, they could aid in guiding laboratory as well as computational experiments in the future.

Functional characterization of CYP2D7 gene variants.

The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.

Association between cytochrome P450 2D6 polymorphisms and body fluid methamphetamine concentrations in Japanese forensic autopsy cases

Methamphetamine (MA) is an illicit stimulant that affects the central nervous system. Cytochrome P450 2D6 (CYP2D6) plays an important role in MA metabolism. Numerous allelic variants confer substantial variation in CYP2D6 activity among individuals. In the present study, we examined the frequencies of CYP2D6 alleles, including CYP2D6*1, *2, *4, *5, *10, *14A, *14B, *18, and *36, and multiplication, in 82 forensic autopsy cases of MA abusers and 567 autopsy cases in which MA was not detected (controls). Ultrarapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) phenotypes were predicted from CYP2D6 genotypes. Of MA abusers, 64 subjects were predicted to be EM, 17 were IM, and 1 was UM. No MA abuser had the predicted PM phenotype. No significant differences in CYP2D6 phenotype frequencies were found between MA abusers and controls. MA and amphetamine (AMP) concentrations were measured in the right heart blood, left heart blood, peripheral external iliac blood, urine, pericardial fluid, and bone marrow of MA abusers. MA concentrations in urine and bone marrow were significantly higher in IM than in EM. AMP concentration was not associated with CYP2D6 phenotype in any body fluid. These results suggest that the MA concentration in body fluids is influenced by CYP2D6 phenotypes in the Japanese population.

Drug-Drug Interactions with Consideration of Pharmacogenetics

Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.

Is There a Link Between Clopidogrel Resistance and Common Risk Factors for Atherosclerosis in Patients with Acute Coronary Syndrome?

The antiplatelet effect of clopidogrel prodrug is characterized by a wide inter-individual variability that has a significant clinical relevance. Among varios factors that are involved in the occurrence of clopidogrel resistance, the genetic polymorphisms play a key role. The aim of the present study was to investigate the impact of some risk factors for atherosclerosis on the antiplatelet effect of clopidogrel in patients with acute coronary syndrome and the possible correlation with metabolizer phenotype of patients based on CYP2C19 polymorfisms. We found a statistically significant correlation (p value [ 0.05) between smoking or dyslipidaemia and the presence of ultrarapid metabolizer phenotype for clopidogrel in our research population.

A cost-effectiveness analysis of maternal CYP2D6 genetic testing to guide treatment for postpartum pain and avert infant adverse events.

Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. Pharmacogenetic testing may be a valuable tool to identify such mothers, but testing can be costly. The objective of the study was to determine the incremental costs of genotyping to avert neonatal adverse events during maternal pharmacotherapy. A cost-effectiveness analysis, using a decision model, was performed with a hypothetical cohort of prenatal subjects. Parameter estimates, costs and ranges for sensitivity analyses were ascertained from the literature and expert opinion. Sensitivity analyses were conducted to assess the robustness of the results. Probabilistic sensitivity analysis revealed an incremental cost-effectiveness (ICER) of $10 433 (Canadian dollars) for genotyping compared to no genotyping per adverse event averted. Results were sensitive to hospital admission costs. The ICER was lower when evaluating only subjects having caesarean deliveries or those from ethnic populations known to have a high prevalence of ultra-rapid metabolizers. Although genotyping to guide pharmacotherapy was not cost saving, the cost to avert an infant adverse event may represent good value for money in specific populations. With a growing demand for personalized medicine, these findings are relevant for decision makers, clinicians and patients.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach

IntroductionOpioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. MethodsWe analyzed a patient who reported discomfort at daily buprenorphine dose of 24mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. ResultsAt the 24mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. ConclusionPharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.