CYP2D6 Poor Metabolizers Research Articles

Multidisciplinary Consulting Team for Complicated Cases of Neurodevelopmental and Neurobehavioral Disorders: Assessing the Opportunities and Challenges of Integrating Pharmacogenomics into a Team Setting.

Neurodevelopmental disorders have steadily increased in incidence in the United States. Over the past decade, there have been significant changes in clinical diagnoses and treatments some of which are due to the increasing adoption of pharmacogenomics (PGx) by clinicians. In this pilot study, a multidisciplinary team at the Arkansas Children’s Hospital North West consulted on 27 patients referred for difficult-to-manage neurodevelopmental and/or neurobehavioral disorders. The 27 patients were evaluated by the team using records review, team discussion, and pharmacogenetic testing. OneOme RightMed® (Minneapolis, MN, USA) and the Arkansas Children’s Hospital comprehensive PGx test were used for drug prescribing guidance. Of the 27 patients’ predicted phenotypes, the normal metabolizer was 11 (40.8%) for CYP2C19 and 16 (59.3%) for CYP2D6. For the neurodevelopmental disorders, the most common comorbid conditions included attention-deficit hyperactivity disorder (66.7%), anxiety disorder (59.3%), and autism (40.7%). Following the team assessment and PGx testing, 66.7% of the patients had actionable medication recommendations. This included continuing current therapy, suggesting an appropriate alternative medication, starting a new therapy, or adding adjunct therapy (based on their current medication use). Moreover, 25.9% of patients phenoconverted to a CYP2D6 poor metabolizer. This retrospective chart review pilot study highlights the value of a multidisciplinary treatment approach to deliver precision healthcare by improving physician clinical decisions and potentially impacting patient outcomes. It also shows the feasibility to implement PGx testing in neurodevelopmental/neurobehavioral disorders.

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients.

The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

Prolonged coma due to amitriptyline overdose and genetic polymorphism: a case report

BackgroundReduced consciousness has a wide variety of possible causes, not infrequently being toxic in nature. An intoxication might be obvious, but in this paper an unexpected case with a tricyclic antidepressant is presented.Case presentationA 76-year-old caucasian female was found unconscious. Primary diagnostic evaluation, including a negative drugs of abuse test, did not give direction to any clear cause. Yet an intraventricular conductive disorder with widening of the QRS complex and electroencephalogram abnormalities did suggest a possible drug effect. Heteroanamnestic information led to the suspicion of an amitriptyline intoxication, which was confirmed by further laboratory analysis. The patient remained comatose for several days. High concentrations of amitriptyline indicated a large overdose of amitriptyline and, in combination with a cytochrome P450 2D6 poor metabolizer status, could explain the long persistence of her comatose state.ConclusionWe present a tricyclic antidepressant intoxication, where the patient is thought to have taken a large amount of amitriptyline at once, which, in combination with a cytochrome P450 2D6 poor metabolizer status, led to an unusual long persistence of her coma.

CYP2D6 Genetic Variation and Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis.

BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs).ResultsTwelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associations. Seventeen studies were included in the meta-analysis with clinical data of 2,041 patients, including 93 poor metabolizers (PMs), 633 intermediate metabolizers (IMs), 1,272 normal metabolizers (NMs), and 30 UMs. Overall, we did not find associations in any of the comparisons made. The estimated pooled standardized differences for the following comparisons were (i) PM versus NM; weight = –0.07 (95%CI: –0.49 to 0.35, p = 0.74), BMI = 0.40 (95%CI: –0.19 to 0.99, p = 0.19). (ii) IM versus NM; weight = 0.09 (95% CI: –0.04 to 0.22, p = 0.16) and BMI = 0.09 (95% CI: –0.24 to 0.41, p = 0.60). (iii) UM versus EM; weight = 0.01 (95% CI: –0.37 to 0.40, p = 0.94) and BMI = –0.08 (95%CI: –0.57 to 0.42, p = 0.77).ConclusionOur systematic review of cohort studies suggested that CYP2D6 poor metabolizers have higher BMI than normal metabolizers, but the data of cross-sectional studies and the meta-analysis did not show this association. Although our review and meta-analysis constitutes one of the largest studies with comprehensively genotyped samples, the literature is still limited by small numbers of participants with genetic variants resulting in poor or UMs status. We need further studies with larger numbers of extreme metabolizers to establish its clinical utility in antipsychotic treatment. CYP2D6 is a key gene for personalized prescribing in mental health.

Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment.

Introduction:In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid.Methods:We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Eleven evaluable patients were included.Results:Treatment with tamoxifen and probenecid resulted in a 26% increase of endoxifen area under the plasma concentration–time curve from 0 to 24 h (AUC0–24h) compared to tamoxifen monotherapy (95% confidence interval [CI]: 8–46%; p < 0.01), while the maximum observed endoxifen concentration increased with 24% (95% CI: 7–44%; p < 0.01). The metabolic ratio of endoxifen to tamoxifen increased with 110% (95% CI: 82–143%; p < 0.001) after the addition of probenecid.Conclusion:Probenecid resulted in a clinically relevant increase of endoxifen concentrations in breast cancer patients treated with adjuvant tamoxifen. This combination therapy could provide a solution for patients with a CYP2D6-poor metabolizer phenotype or endoxifen concentrations below the threshold despite earlier tamoxifen dose.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs.

The Dutch Pharmacogenetics Working Group (DPWG) guideline presented here, presents the gene-drug interaction between the genes CYP2C19 and CYP2D6 and antidepressants of the selective serotonin reuptake inhibitor type (SSRIs). Both genes' genotypes are translated into predicted normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), or ultra-rapid metabolizer (UM). Evidence-based dose recommendations were obtained, based on a structured analysis of published literature. In CYP2C19 PM patients, escitalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 75% of the normal maximum dose. Escitalopram should be avoided in UM patients. In CYP2C19 PM patients, citalopram dose should not exceed 50% of the normal maximum dose. In CYP2C19 IM patients, this is 70% (65-75%) of the normal maximum dose. In contrast to escitalopram, no action is needed for CYP2C19 UM patients. In CYP2C19 PM patients, sertraline dose should not exceed 37.5% of the normal maximum dose. No action is needed for CYP2C19 IM and UM patients. In CYP2D6 UM patients, paroxetine should be avoided. No action is needed for CYP2D6 PM and IM patients. In addition, no action is needed for the other gene-drug combinations. Clinical effects (increase in adverse events or decrease in efficacy) were lacking for these other gene-drug combinations. DPWG classifies CYP2C19 genotyping before the start of escitalopram, citalopram, and sertraline, and CYP2D6 genotyping before the start of paroxetine as "potentially beneficial" for toxicity/effectivity predictions. This indicates that genotyping prior to treatment can be considered on an individual patient basis.

The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Effects of Cytochrome P450 and Transporter Polymorphisms on the Bioavailability and Safety of Dutasteride and Tamsulosin.

Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with CYP2D6 poor metabolizers (PMs) that receive CYP3A4 inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, CYP2D6 PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC (p = 0.004), higher t1/2 (p = 0.008), and lower Cl/F (p = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher tmax than fasting individuals. Nominally significant associations were observed between dutasteride exposure and CYP3A4 and CYP3A5 genotype and between tamsulosin and ABCG2, CYP3A5, and SLC22A1 genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.

Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients.

Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations. We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra-rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard-dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain-related hospital encounters. Most patients with cancer (n= 34,675, 56%) received multiple opioids (average 2.8± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n= 105), IM/PMs received a similar number of opioids (3.4± 1.4) as NMs (3.3± 1.9). However, IM/PMs were significantly more likely to experience pain-related hospital encounters compared with NMs, independent of other variables (odds ratio [OR]= 5.4; 95% confidence interval [CI], 1.2-23.6; p=.03). IM/PMs were also more likely to be treated with later-line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR=3.3; 95% CI, 1.1-9.8; p=.03). CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first-line opioids like codeine, tramadol, or standard-dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management. Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6-dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain-related hospitalizations and more frequently required the potent non-CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common "first-line" CYP2D6-metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain-related patient outcomes.

Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests.

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10-300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10-4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10-38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

Brexpiprazole Pharmacokinetics in CYP2D6 Poor Metabolizers: Using Physiologically Based Pharmacokinetic Modeling to Optimize Time to Effective Concentrations

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs). A PBPK model was constructed, verified, and validated against brexpiprazole clinical data, and simulations of 500 subjects were performed to establish the median time to effective concentrations in EMs and PMs. The PBPK simulations captured brexpiprazole PK well and demonstrated significant differences in the time to effective concentrations between EMs and PMs according to the label-recommended titration. Additionally, these simulations suggest that CYP2D6 PMs consistently achieve lower minimum concentrations during the dosing interval than CYP2D6 EMs. Simulations using an alternative dosing strategy of twice-daily dosing (as opposed to once daily) in PMs during the first week of brexpiprazole dosing yielded more consistent plasma concentrations between EMs and PMs, without exceeding the area under the plasma concentration-time curve observed in the EMs. Taken together, the results of these PBPK simulations suggest that product labeling for brexpiprazole titration in CYP2D6 PMs likely overcompensates for the decreased clearance seen in this population. We propose an alternative dosing strategy that decreases the time to effective concentrations and recommend a reevaluation of steady-state PK in this population to potentially allow for higher daily doses in CYP2D6 PMs.

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone.

Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.

Long-Term Hematologic Response to Oral Eliglustat in Treatment-Naive Patients with Gaucher Disease Type 1: Final Results from a Phase 2 and the Phase 3 Engage Trials

Introduction:Gaucher disease is caused by deficient activity of the lysosomal enzyme acid β-glucosidase, leading to accumulation of glucosylceramide primarily in macrophages (Gaucher cells). Thrombocytopenia, anemia, hepatosplenomegaly, and skeletal disease are common presenting symptoms and hematologists often identify and manage the disease. Eliglustat is an oral substrate reduction therapy approved as first-line treatment for adults with Gaucher disease type 1 (GD1) who have poor, intermediate, or extensive CYP2D6-metabolizer phenotypes (>90% of patients). Unlike enzyme replacement therapy (the historic standard of care), which supplements lysosomal acid β-glucosidase in mononuclear phagocytes and is administered in biweekly infusions, oral eliglustat reduces glucosylceramide accumulation by partially inhibiting glucosylceramide synthase.Methods:We report on improvements in hemoglobin concentration and platelet count in two completed clinical trials of eliglustat in treatment-naïve adults with GD1: an open-label Phase 2 trial (N=26, NCT00358150), for which 8-year data are available, and a randomized, placebo-controlled Phase 3 trial (ENGAGE, N=40, NCT00891202) for which 4.5-year data are available. Both trials were sponsored by Sanofi Genzyme.Results:In the Phase 2 trial, the primary endpoint was met after 1 year, with 77% of patients improving in at least 2 of 3 main efficacy parameters (spleen volume, hemoglobin level, and platelet count) (Lukina et al. Blood 2010;116:816). Improvements continued or were maintained throughout the trial. Among patients with 8 years of data (n=19), mean (±SD) hemoglobin level and mean platelet count increased by 2.1±1.7 g/dL (from 11.3±1.6 to 13.4±1.3 g/dL) and 110% (from 67.5±21.1 to 130.7±59.8 x109/L), respectively, after 8 years of eliglustat. In the Phase 3 ENGAGE trial, all primary and secondary endpoints were met, with clinically meaningful improvements from baseline in platelet and hemoglobin levels and spleen and liver volumes at 9 months in eliglustat- but not placebo-treated patients (Mistry et al. JAMA 2015;313;695). During the trial extension, in which all patients received eliglustat, patients switching from placebo had the same magnitude and time course of improvement during the first 9 months as was seen with eliglustat patients in the primary analysis and all patients continued to improve over time with continued eliglustat treatment. Among patients with 4.5 years of eliglustat treatment (n=14), mean (±SD) hemoglobin level increased by 1.4±1.31 g/dL (from 12.0±2.0 g/dL to 13.4±1.9 g/dL) and mean platelet count increased by 87% (from 69.6±18.5 to 122.6±34.1 x109/L). In both trials, hematologic improvements were accompanied by clinically significant decreases in spleen and liver volumes, improvements in bone parameters, and substantive reductions in Gaucher disease biomarkers. In both trials, eliglustat was generally well-tolerated, with three withdrawals due to adverse events in the Phase 2 trial (one of which was considered related to eliglustat) and no withdrawals due to adverse events during the ENGAGE trial. Most adverse events in both trials were non-serious, considered unrelated to eliglustat, and either mild or moderate in severity.Conclusions:In previously untreated patients with GD1, clinically meaningful improvements in hematologic parameters continued or were maintained over time after 8 years of treatment with eliglustat in the Phase 2 trial and after 4.5 years of eliglustat in the Phase 3 ENGAGE trial. DisclosuresLau:Sanofi Genzyme: Other: Principal Investigator in the eliglustat Phase 2 and ENGAGE clinical trials . Lukina:Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE clinical trials; receives travel reimbursement; Shire: Honoraria, Other: travel reimbursement. Mistry:Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Principal investigator in the eliglustat ENGAGE and ENCORE clinical trials; received travel reimbursement, Research Funding. Wu:Sanofi Genzyme: Employment. Gaemers:Sanofi Genzyme: Employment. Peterschmitt:Sanofi Genzyme: Employment.

Impact of CYP2D6 Genetic Variation on Radical Cure of Plasmodium vivax Malaria.

Plasmodium vivax (P. vivax) is the most widespread human malaria parasite, with 2.5 billion people at risk of infection worldwide. P. vivax forms liver hypnozoites, which trigger further symptomatic episodes (relapses) weeks or months after the initial episode. Radical cure of vivax malaria requires hypnozoitocide therapy to prevent relapses. The two US Food and Drug Administration (FDA)-approved hypnozoiticides for human use, primaquine, and tafenoquine, are pro-drugs, that require in vivo conversion into metabolites with redox activity. This mini-review focuses on the association between CYP2D6-mediated hydroxylation and hypnozoitocide efficacy of primaquine and tafenoquine. Studies in murine models show that the antimalarial activity of primaquine and tafenoquine is abolished by CYP2D knock-out and partially restored by knock-in of humanized CYP2D6. Human studies explored the impact of CYP2D6 genetic variation and genotype-inferred CYP2D6 phenotype on anti-relapse efficacy. Most, but not all, studies with primaquine report higher rates of relapse in patients with decreased CYP2D6 activity (activity scores (AS) ≤1) compared to normal activity (AS≥1.5). Potential factors for discordance among studies include risk of reinfection in endemic areas, adherence to primaquine-treatment, assignment of CYP2D6 phenotypes based on CYP2D6 polymorphism and choice of AS values for dichotomizing the study cohorts. Tafenoquine anti-relapse efficacy did not differ between patients with AS<1 vs. AS≥1.5 in 2 studies. Absence/small number of poor CYP2D6 metabolizers in AS≤1 groups, combined with lesser dependence of tafenoquine on CYP2D6-mediated conversion into active redox metabolites may account for this result. Additional tafenoquine studies with larger representation of poor CYP2D6 metabolizers are warranted.

Influence of CYP2D6 Phenotypes on the Pharmacokinetics of Aripiprazole and Dehydro-Aripiprazole Using a Physiologically Based Pharmacokinetic Approach.

Background and ObjectivesAripiprazole is an atypical antipsychotic drug that is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which mainly form its active metabolite dehydro-aripiprazole. Because of the genetic polymorphism of CYP2D6, plasma concentrations are highly variable between different phenotypes. In this study, phenotype-related physiologically based pharmacokinetic models were developed and evaluated to suggest phenotype-guided dose adjustments.MethodsPhysiologically based pharmacokinetic models for single dose (oral and orodispersible formulation), multiple dose, and steady-state condition were built using trial data from genotyped healthy volunteers. Based on evaluated models, dose adjustments were simulated to compensate for genetically caused differences.ResultsPhysiologically based pharmacokinetic models were able to accurately predict the pharmacokinetics of aripiprazole and dehydro-aripiprazole according to CYP2D6 phenotypes, illustrated by a minimal bias and a good precision. For single-dose administration, 92.5% (oral formulation) and 79.3% (orodispersible formulation) of the plasma concentrations of aripiprazole were within the 1.25-fold error range. In addition, physiologically based pharmacokinetic steady-state simulations demonstrate that the daily dose for poor metabolizer should be adjusted, resulting in a maximum recommended dose of 10 mg, but no adjustment is necessary for intermediate and ultra-rapid metabolizers.ConclusionsIn clinical practice, CYP2D6 genotyping in combination with therapeutic drug monitoring should be considered to personalize aripiprazole dosing, especially in CYP2D6 poor metabolizers, to ensure therapy effectiveness and safety.

Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data.

IntroductionVortioxetine is an antidepressant primarily metabolized by the polymorphic enzyme cytochrome P450 (CYP) 2D6. A population pharmacokinetic (popPK) model of vortioxetine and its CYP2D6-dependent metabolite was recently published.ObjectiveThe aim of the current study was to assess the predictive performance of the popPK model using vortioxetine concentration measurements from a clinical setting. Furthermore, the study aimed to evaluate the ability of different CYP2D6 phenotype classification systems to provide accurate concentration predictions.MethodsOverall, 1388 patients receiving vortioxetine treatment were identified from a therapeutic drug monitoring (TDM) database in Oslo, Norway; 334 CYP2D6-genotyped patients with 502 serum concentrations of vortioxetine, analysed by a validated ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS) method, were retrospectively included. The performance of the vortioxetine popPK model was tested on the clinical data from the TDM database.ResultsOverall, the model had a good ability to predict vortioxetine concentrations measured in clinical practice, with a slight tendency to overpredict concentrations. Using simulation-based diagnostics, 76% of the prediction-corrected TDM concentrations were within the 90% prediction interval based on 1000 simulated data sets. Prediction-based diagnostics showed the best performance for CYP2D6 poor and ultrarapid metabolizers, with a median prediction error (MDPE) of 12% and 23%, respectively, while the poorest performance was observed for normal metabolizers, with an MDPE of 66%. In the comparison of different CYP2D6 phenotype classification systems, the use of differentiated activity scores for decreased function alleles did not improve the concentration predictions. Grouping the CYP2D6 genotypes into the four conventional phenotype groups provided predictions closest to the TDM measured concentrations.ConclusionTDM data provide a unique insight into real-world clinical practice with vortioxetine. The tendency of the popPK model to overpredict vortioxetine concentrations measured in TDM may be attributed to several factors, including poor treatment compliance for some patients and, to a lesser extent, lack of information on patient characteristics and misspecified CYP2D6 alleles. To optimize personalized therapy with vortioxetine, real-world clinical data sets originating from different ethnicities need to be studied in the future.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01029-7.

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry.

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels

The primary goal of precision medicine is to maximize the benefit‐risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene‐drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA‐PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug‐metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

Influence of Genetic Polymorphisms on the Response to Tramadol, Ibuprofen, and the Combination in Patients With Moderate to Severe Pain After Dental Surgery

PurposeWe aimed to elucidate the influence on analgesic effect of genetic polymorphisms in enzymes responsible for biotransformation of tramadol and ibuprofen or other possible genes involved in their mechanism of action. MethodsThe study population comprised 118 patients from a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial that assessed the analgesic efficacy and tolerability of a single dose of ibuprofen (arginine)/tramadol 400/37.5 mg compared with ibuprofen arginine 400 mg alone, tramadol 50 mg alone, and placebo in patients with moderate to severe pain after dental surgery. We analyzed 32 polymorphisms in the cytochrome P450 (CYP) enzymes COMT, ABCB1, SLC22A1, OPRM1, and SLC22A1. FindingsWe did not find any statistically significant difference among CYP2C9 phenotypes related to ibuprofen response, although CYP2C9 poor metabolizers had a longer effect (higher pain relief at 6 hours). Likewise, we did not find any statistically significant difference among PTGS2 genotypes, contradicting previously publications. ImplicationsThere was not a clear effect of CYP2D6 phenotype on tramadol response, although CYP2D6 poor metabolizers had a slower analgesic effect. Concerning the transport of CYP2D6, we observed a better response in individuals carrying ABCB1 mutated alleles, which might correlate with higher tramadol plasma levels. Finally, we found a statistically significant better response in patients carrying the OPRM1 A118G G allele, which contradicts the previous reports. Measuring the active metabolite O-desmethyl-tramadol formation would be of great importance to better evaluate this association because O-desmethyl-tramadol has a higher μ-opioid receptor affinity compared with the parent drug. EudraCT.ema.europa.eu identifier: 2013-004637-33.