MedGen

Eliglustat is a glucosylceramide synthase inhibitor used in the treatment of Gaucher disease (GD). Eliglustat is indicated for the long-term treatment of adult individuals with Gaucher disease type 1 (GD1) who are CYP2D6 normal metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test. Gaucher disease is an autosomal recessive metabolic disorder characterized by accumulation of glucosylceramide (a sphingolipid also known as glucocerebroside) within lysosomes. This is caused by a malfunction of the enzyme acid beta-glucosidase, encoded by the gene GBA. Type 1 GD may present in childhood or adulthood with symptoms including bone disease, hepatosplenomegaly, thrombocytopenia, anemia and lung disease and –– unlike Gaucher types 2 and 3 –– does not directly affect the central nervous system primarily. Eliglustat, a ceramide mimic, inhibits the enzyme that synthesizes glucosylceramides (UDP-Glucose Ceramide Glucosyltransferase), thereby reducing the accumulation of these lipids in the lysosome. Eliglustat is broken down to inactive metabolites by CYP2D6 and, to a lesser extent, CYP3A. The dosage of eliglustat is based on the individual’s CYP2D6 metabolizer status. Individuals with normal CYP2D6 activity are termed normal metabolizers (NM), those with reduced activity are termed intermediate metabolizers (IM), and if activity is absent, poor metabolizers (PM). The FDA-approved drug label for eliglustat provides specific dosage guidelines based on their CYP2D6 status and concomitant usage of CYP2D6 or CYP3A inhibitors, and states that hepatic and renal function should also be considered when determining the appropriate dosage. The label also states that CYP2D6 ultrarapid metabolizers (UM) may not achieve adequate concentrations of eliglustat for a therapeutic effect, and that for individuals for whom a CYP2D6 genotype cannot be determined, a specific dosage cannot be recommended. Dosing recommendations for eliglustat have also been published by the Dutch Pharmacogenetics Working Group (DPWG) based on CYP2D6 metabolizer type and include dose adjustments for dosing eliglustat with medications that alter CYP2D6 and or CYP3A function. [from Medical Genetics Summaries]

Ondansetron and tropisetron are highly specific and selective members of the 5-HT3 receptor antagonists and are used for the prevention of chemotherapy-induced, radiation-induced and postoperative nausea and vomiting. While tropisetron is extensively metabolized by CYP2D6 to inactive metabolites, ondansetron is metabolized by multiple cytochrome P450 enzymes including CYP3A4, CYP1A2 and CYP2D6, though there is substantial data to support a major role of CYP2D6 in ondansetron metabolism. For both drugs, there is evidence linking the CYP2D6 genotype with phenotypic variability in drug efficacy. CYP2D6 ultrarapid metabolizers may have increased metabolism of the drugs, resulting in decreased drug efficacy. There are suitable alternatives to ondansetron and tropisetron that are not affected by CYP2D6 metabolism. Therapeutic guidelines for ondansetron and tropisetron based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Ondansetron and tropisetron are highly specific and selective members of the 5-HT3 receptor antagonists and are used for the prevention of chemotherapy-induced, radiation-induced and postoperative nausea and vomiting. While tropisetron is extensively metabolized by CYP2D6 to inactive metabolites, ondansetron is metabolized by multiple cytochrome P450 enzymes including CYP3A4, CYP1A2 and CYP2D6, though there is substantial data to support a major role of CYP2D6 in ondansetron metabolism. For both drugs, there is evidence linking the CYP2D6 genotype with phenotypic variability in drug efficacy. CYP2D6 ultrarapid metabolizers may have increased metabolism of the drugs, resulting in decreased drug efficacy. There are suitable alternatives to ondansetron and tropisetron that are not affected by CYP2D6 metabolism. Therapeutic guidelines for ondansetron and tropisetron based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Primaquine is a potent antimalarial medication indicated for the radical cure of malaria caused by Plasmodium vivax (P. vivax) and Plasmodium ovale (P. ovale) species. Malaria is a blood borne infection caused by infection of Plasmodium parasites that is spread by mosquitos. The P. vivax and P. ovale species present a particular challenge to treat because the parasitic life cycle includes a dormant, liver-specific stage that is not susceptible to other antimalarial medications. Thus, primaquine is often used with other therapies such as chloroquine or artemisinin-based medicines that target the reproductive, active forms of the parasite. Primaquine is also used to prevent transmission of malaria caused by Plasmodium falciparum (P. falciparum) species. A single, low dose (SLD) of primaquine has gametocidal activity, which does not cure the individual but does provide malaria transmission control. Primaquine is a pro-drug that must be activated by the cytochrome P450 (CYP) enzyme system. Metabolism by the cytochrome P450 member 2D6 (CYP2D6) and cytochrome P450 nicotinamide adenine dinucleotide phosphate (NADPH):oxidoreductase (CPR) generates 2 hydroxylated active metabolites that generate hydrogen peroxide (H2O2). This causes significant oxidative stress to the malarial parasite and the host human cells. Individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient are particularly susceptible to oxidative stress and may experience acute hemolytic anemia (AHA). Before starting a course of primaquine, individuals should be tested for G6PD deficiency to ensure safe administration. According to the FDA-approved drug label, individuals with severe G6PD deficiency should not take primaquine. The World Health Organization (WHO) recommends that individuals with G6PD deficiency should be treated with a modified course of primaquine therapy. The recommended course for individuals with G6PD deficiency is a single dose once per week for 8 weeks, while the standard course is daily administration for 14 days. The Clinical Pharmacogenetics Implementation Consortium (CPIC) reports that the risk of adverse effects of primaquine therapy for G6PD-deficient individuals is dose-dependent, with the SLD regimen presenting the least risk. Primaquine is contraindicated during pregnancy and is not recommended for breastfeeding individuals when the G6PD status of the baby is unknown. Primaquine is not approved for individuals under 6 months of age. Individuals with acute illness that are prone to granulocytopenia or individuals taking another hemolytic medication are also contraindicated from taking primaquine. [from Medical Genetics Summaries]

Deutetrabenazine (brand name Austedo) is used to treat chorea associated with Huntington disease (HD) and tardive dyskinesia (TD). Both HD and TD are types of involuntary movement disorders. The recommended starting dose is 6 mg once daily for individuals with HD and 12 mg per day (6 mg twice daily) for individuals with TD. The maximum recommended daily dosage for both conditions is 48 mg (24 mg, twice daily). The active metabolites of deutetrabenazine are reversible inhibitors of vesicular monoamine transporter 2 (VMAT2). The VMAT2 protein transports the uptake of monoamines, such as dopamine, into the nerve terminal. The inhibition of VMAT2 leads to a depletion of pre-synaptic dopamine and reduces the amount of dopamine realized when that neuron fires. This is thought to lead to fewer abnormal, involuntary movements. The CYP2D6 enzyme converts the active metabolites of deutetrabenazine to minor, reduced activity metabolites. Individuals who have no CYP2D6 activity (“CYP2D6 poor metabolizers”) are likely to have a 3- to 4-fold increased exposure to active metabolites, compared with normal metabolizers, following the recommended standard doses of deutetrabenazine. The 2018 FDA-approved drug label for deutetrabenazine states that the daily dose of deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg) for individuals who are CYP2D6 poor metabolizers or concurrently taking a strong CYP2D6 inhibitor (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion). In addition, the drug label cautions that tetrabenazine, a closely related VMAT2 inhibitor, causes QT prolongation. Therefore, a clinically relevant QT prolongation may occur in some individuals treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor. [from Medical Genetics Summaries]

Serotonin reuptake inhibitor antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and serotonin modulators with SSRI-like properties are pharmacotherapy options for major depressive and anxiety disorders. Inadequate response and treatment-related adverse events are known challenges in antidepressant therapy. Genetic variations in genes encoding the drug metabolizing enzymes, CYP2D6, CYP2C19 and CYP2B6, have been shown to alter antidepressant biotransformation, which may potentially affect dosing, efficacy, and tolerability. [from PharmGKB]

Serotonin reuptake inhibitor antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and serotonin modulators with SSRI-like properties are pharmacotherapy options for major depressive and anxiety disorders. Inadequate response and treatment-related adverse events are known challenges in antidepressant therapy. Genetic variations in genes encoding the drug metabolizing enzymes, CYP2D6, CYP2C19 and CYP2B6, have been shown to alter antidepressant biotransformation, which may potentially affect dosing, efficacy, and tolerability. [from PharmGKB]

Imipramine is a tricyclic antidepressant used in the treatment of several psychiatric disorders including major depression, obsessive-compulsive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Imipramine may also be useful as an adjunctive treatment in the management of panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting). Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, a1-adrenergic, and muscarinic receptors), side effects are common. As such, more specific selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of them. However, TCAs still have an important use in specific types of depression and other conditions. Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, also a tricyclic antidepressant. Further metabolism is catalyzed by CYP2D6. Individuals who are "CYP2D6 ultrarapid metabolizers" carry more than two normal function alleles (i.e., multiple copies), whereas individuals who are "CYP2C19 ultrarapid metabolizers" carry two increased function alleles. Individuals who are CYP2D6 or CYP2C19 "poor metabolizers" carry two no function alleles for CYP2D6 or CYP2C19, respectively. The FDA-approved drug label for imipramine states that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. Their recommendations include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is going to be co-administered with another drug known to be an inhibitor of CYP2D6. In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) made dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 genotypes. Amitriptyline and nortriptyline were used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, it may be reasonable to apply the recommendations to other tricyclics, including imipramine. For CYP2D6 ultrarapid metabolizers, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared to normal metabolizers) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 intermediate metabolizers, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 poor metabolizers, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. For CYP2C19 ultrarapid metabolizers, CPIC recommends avoiding the use of tertiary amines (e.g., imipramine) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 poor metabolizers, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 poor metabolizers, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects. [from Medical Genetics Summaries]

Amitriptyline is a tricyclic that can be identified by the tertiary amine in its chemical structure. Tricyclics are commonly prescribed for psychological disorders and pain management. Genetic variants in both cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) may affect treatment success of amitriptyline or other tricyclics with the tertiary amine functional group. Patients with poor metabolizer variants of either CYP2D6 or CYP2C19 may require reductions in dose or alternative agents in order to circumvent common adverse anticholinergic, central nervous system, or cardiac effects. Guidelines regarding the use of pharmacogenomic tests in dosing for amitriptyline and other tricyclics have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Tramadol, an opioid analgesic, is used for the treatment of pain. It is metabolized by cytochrome P450-2D6 (CYP2D6) to O-desmethyltramdol, an active metabolite with pain-relief action. The CYP2D6 gene has many polymorphisms that result in different enzyme activities. An individual can be an ultrarapid, normal, intermediate, or poor metabolizer of tramadol, based on their CYP2D6 genotype. The CYP2D6 ultrarapid phenotype is associated with a higher risk of severe toxicity when treated with tramadol, due to increased metabolism of tramadol and thus enhanced formation of the active metabolite. Conversely, the CYP2D6 poor metabolizer phenotype is associated with ineffective pain relief from tramadol treatment due to reduced formation of the active metabolite. Accordingly, therapeutic recommendations for tramadol based on an individual’s CYP2D6 genotype have been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in Clinical Pharmacology and Therapeutics and are available on the PharmGKB website. [from PharmGKB]

Thioridazine is an antipsychotic used in the treatment of schizophrenia and psychosis. Its use is reserved for patients who have failed to respond to or cannot tolerate other antipsychotics. Thioridazine has been shown to prolong the QT interval (the time taken for the heart ventricles to depolarize and repolarize) in a dose related manner. Drugs with this potential have been associated with the life-threatening ventricular tachycardia, "torsades de pointes". The CYP2D6 enzyme is involved in metabolizing thioridazine. About 7% of the population has reduced enzyme activity because of variants in the CYP2D6 gene. In individuals with low CYP2D6 activity, standard doses of thioridazine may lead to higher drug levels in the plasma, and increase the risk of cardiac arrhythmias. The FDA-approved drug label for thioridazine states that thioridazine is contraindicated in individuals who are known to have reduced levels of CYP2D6 activity. The label also states it is contraindicated to coadminister thioridazine with drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) or inhibit the metabolism of thioridazine (e.g., fluvoxamine, propranolol, and pindolol). [from Medical Genetics Summaries]

Tamoxifen is a selective estrogen receptor modulator (SERM) utilized in breast cancer treatment. Tamoxifen is extensively metabolized, in part by CYP2D6. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. The CPIC guideline and supplement summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype. Therapeutic guidelines for tamoxifen based on CYP2D6 genotype have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and the PharmGKB website. [from PharmGKB]

Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype–directed dosing of tricyclic antidepressants. [from Clinical Pharmacogenetics Implementation Consortium]

Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia (TRS). Clozapine is also used to reduce the risk of recurrent suicidal behavior in individuals with schizophrenia or schizoaffective disorder. Compared with typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill individuals who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood cell counts (WBC) and absolute neutrophil counts (ANC), and in the US, the FDA requires that individuals receiving clozapine be enrolled in a computer-based registry. There is also a propensity for clozapine use to induce metabolic effects, resulting in substantial weight gain. Clozapine is metabolized in the liver by the cytochrome P450 (CYP450) superfamily of enzymes. The CYP1A2 enzyme is the main CYP enzyme involved in clozapine metabolism, and CYP1A2 activity is a potential determinant of clozapine dose requirements. Other CYP enzymes involved in clozapine metabolism include CYP2D6, CYP3A4, and CYP2C19. The FDA-approved drug label states that a subset of the population (2–10%) have reduced activity of CYP2D6 (“poor metabolizers”[PMs]) and these individuals may develop higher than expected plasma concentrations of clozapine with typical standard doses. Therefore, the FDA states that a dose reduction may be necessary in individuals who are CYP2D6 PMs. However, the Dutch Pharmacogenetics Working Group (DPWG) does not recommend dose alterations based on CYP2D6 genotype, though the gene-drug interaction is acknowledged. The DPWG further states that there is not a gene-drug interaction between CYP1A2 and clozapine due to the limited effect of known genetic variants on CYP1A2 function. Consequently, neither the FDA nor the DPWG recommend dose alterations based on CYP1A2 genotype. Additionally, clozapine clearance is affected by gender, tobacco use, and ethnicity, with further contributions from pharmacologic interactions. Females have lower CYP1A2 enzyme activity than males. Non-smokers have lower CYP1A2 activity than smokers and Asians and Amerindians have lower activity than Caucasians. Clozapine clearance can also be affected by co-medications that induce or inhibit CYP1A2 and the presence of inflammation or obesity. [from Medical Genetics Summaries]

Nortriptyline is a tricyclic that can be identified by the secondary amine in its chemical structure. Tricyclics are commonly prescribed for psychological disorders and pain management. Genetic variants in cytochrome P450 2D6 (CYP2D6) may affect treatment success of nortriptyline or other tricyclics with the secondary amine functional group. Patients with poor metabolizer variants of CYP2D6 may require reductions in dose or alternative agents in order to circumvent common adverse anticholinergic, central nervous system, or cardiac effects. Guidelines regarding the use of pharmacogenomic tests in dosing for nortriptyline and other tricyclics have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Codeine, an opioid analgesic, is used for the treatment of pain. It is metabolized by cytochrome P450-2D6 (CYP2D6) to morphine, an active metabolite with pain-relief action. The CYP2D6 gene has many polymorphisms that result in different enzyme activities. An individual can be an ultrarapid, normal, intermediate, or poor metabolizer of codeine, based on their CYP2D6 genotype. The CYP2D6 ultrarapid phenotype is associated with a higher risk of severe toxicity when treated with codeine, due to increased metabolism of codeine and thus enhanced morphine formation. Conversely, the CYP2D6 poor metabolizer phenotype is associated with ineffective pain relief from codeine treatment due to reduced formation of morphine. Accordingly, therapeutic recommendations for codeine based on an individual’s CYP2D6 genotype have been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in Clinical Pharmacology and Therapeutics and are available on the PharmGKB website. [from PharmGKB]