MedGen

Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700. [from OMIM]

CYP2C8 is involved in the metabolism of a multitude of chemically diverse medications, including nonsteroidal antiinflammatory drugs, thiazolidinediones, and chemotherapeutic agents (summary by Zhou et al., 2017). Backman et al. (2016) reviewed the role of CYP2C8 in clinically relevant drug interactions. [from OMIM]

ANOA is an autosomal recessive neurologic disorder characterized by onset of visual and hearing impairment in the first or second decades (summary by Paul et al., 2017). [from OMIM]

Lacosamide (brand name Vimpat) is an antiseizure drug indicated for adjunctive therapy for partial-onset seizures in pediatric and adult patients with epilepsy. Lacosamide is thought to work by selectively enhancing slow inactivation of voltage-dependent sodium channels. This stabilizes the neuronal membrane and suppresses the repetitive neuronal firing associated with seizures. Several cytochrome P450 (CYP) enzymes are involved in metabolizing active lacosamide to an inactive metabolite, including CYP2C19. Individuals who have no CYP2C19 enzyme activity are known as "CYP2C19 poor metabolizers". The FDA-approved drug label for lacosamide cites a small study that found plasma levels of lacosamide were similar in CYP2C19 poor metabolizers (n=4) and normal (extensive) metabolizers (n=8). Therefore, the recommended standard doses of lacosamide may be used for CYP2C19 poor metabolizers. [from Medical Genetics Summaries]

Brivaracetam (brand name Briviact) is an antiseizure drug used in the treatment of partial-onset (focal) epilepsy in adults. It is thought to act by binding to a synaptic vesicle glycoprotein, SV2A, and reducing the release of neurotransmitters. Brivaracetam is primarily metabolized by hydrolysis, via amidase enzymes, to an inactive metabolite. To a lesser extent, it is also metabolized by a minor metabolic pathway via CYP2C19-dependent hydroxylation. Individuals who have no CYP2C19 enzyme activity, "CYP2C19 poor metabolizers", will have a greater exposure to standard doses of brivaracetam. Because they are less able to metabolize the drug to its inactive form for excretion, they may have an increased risk of adverse effects. The most common adverse effects of brivaracetam therapy include sedation, fatigue, dizziness, and nausea. The recommended starting dosage for brivaracetam monotherapy or adjunctive therapy is 50 mg twice daily (100 mg per day). Based on how the individual responds, the dose of brivaracetam may be decreased to 25 mg twice daily (50 mg per day) or increased up to 100 mg twice daily (200 mg per day). The FDA-approved drug label for brivaracetam states that patients who are CYPC19 poor metabolizers, or are taking medicines that inhibit CYP2C19, may require a dose reduction. Approximately 2% of Caucasians, 4% of African Americans, and 14% of Chinese are CYP2C19 poor metabolizers. [from Medical Genetics Summaries]

Flibanserin is indicated for the treatment of “hypoactive sexual desire disorder” (HSDD) in premenopausal women. It is the first drug to be approved by the FDA for female sexual dysfunction. Flibanserin acts on central serotonin receptors and was initially developed to be an antidepressant. Although it was not effective for depression, flibanserin did appear to increase sex drive. The use of flibanserin is limited by modest efficacy and the risk of severe hypotension and syncope (fainting). This risk is increased by alcohol, and by medications that inhibit CYP3A4 (the primary enzyme that metabolizes flibanserin). Consequently, alcohol use is contraindicated during flibanserin therapy, and flibanserin is contraindicated in individuals taking moderate or strong CYP3A4 inhibitors, which include several antibiotics, antiviral agents, cardiac drugs, and grapefruit juice. The CYP2C19 enzyme also contributes to the metabolism of flibanserin, and individuals who lack CYP2C19 activity (“CYP2C19 poor metabolizers”) have a higher exposure to flibanserin than normal metabolizers. The risk of hypotension, syncope, and CNS depression may be increased in individuals who are CYP2C19 poor metabolizers, according to the FDA-approved drug label, which also states that approximately 2–5% of Caucasians and Africans and 2–15% of Asians are CYP2C19 poor metabolizers. However, the drug label does not provide alternative dosing for poor metabolizers. The standard recommended dosage of flibanserin is 100 mg once per day, taken at bedtime. [from Medical Genetics Summaries]

Proton pump inhibitors (PPIs) inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects. CYP2C19 intermediate (IMs) and poor metabolizers (PMs) have been associated with decreased clearance and increased plasma concentrations of the first-generation PPIs, which leads to increased treatment success compared to CYP2C19 normal metabolizers (NMs). However, higher exposure and long-term use of PPIs have also been associated with adverse effects. CYP2C19 ultrarapid (UMs) and rapid metabolizers (RMs) have shown increased metabolism compared to NMs, which may increase the risk of treatment failure. Guidelines regarding the use of pharmacogenomic tests in dosing for PPIs have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and PharmGKB websites. The CPIC guideline provides specific therapeutic recommendations for four PPIs (omeprazole, lansoprazole, pantoprazole, and dexlansoprazole) based on CYP2C19 genotype. [from PharmGKB]

Proton pump inhibitors (PPIs) inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects. CYP2C19 intermediate (IMs) and poor metabolizers (PMs) have been associated with decreased clearance and increased plasma concentrations of the first-generation PPIs, which leads to increased treatment success compared to CYP2C19 normal metabolizers (NMs). However, higher exposure and long-term use of PPIs have also been associated with adverse effects. CYP2C19 ultrarapid (UMs) and rapid metabolizers (RMs) have shown increased metabolism compared to NMs, which may increase the risk of treatment failure. Guidelines regarding the use of pharmacogenomic tests in dosing for PPIs have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and PharmGKB websites. The CPIC guideline provides specific therapeutic recommendations for four PPIs (omeprazole, lansoprazole, pantoprazole, and dexlansoprazole) based on CYP2C19 genotype. [from PharmGKB]

Proton pump inhibitors (PPIs) inhibit the final pathway of acid production, which leads to inhibition of gastric acid secretion. PPIs are widely used in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. The first-generation inhibitors omeprazole, lansoprazole and pantoprazole are extensively metabolized by the cytochrome P450 isoform CYP2C19 and to a lesser extent by CYP3A4. The second-generation PPI dexlansoprazole appears to share a similar metabolic pathway to lansoprazole. CYP2C19 genotypes have been linked to PPI exposure and in turn to PPI efficacy and adverse effects. CYP2C19 intermediate (IMs) and poor metabolizers (PMs) have been associated with decreased clearance and increased plasma concentrations of the first-generation PPIs, which leads to increased treatment success compared to CYP2C19 normal metabolizers (NMs). However, higher exposure and long-term use of PPIs have also been associated with adverse effects. CYP2C19 ultrarapid (UMs) and rapid metabolizers (RMs) have shown increased metabolism compared to NMs, which may increase the risk of treatment failure. Guidelines regarding the use of pharmacogenomic tests in dosing for PPIs have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and PharmGKB websites. The CPIC guideline provides specific therapeutic recommendations for four PPIs (omeprazole, lansoprazole, pantoprazole, and dexlansoprazole) based on CYP2C19 genotype. [from PharmGKB]

Clobazam is approved by the FDA to treat seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older. The drug is widely used in the chronic treatment of focal and generalized seizures, and has application in the treatment of diverse epilepsy syndromes, including epileptic encephalopathies other than LGS, such as Dravet syndrome. Lennox-Gastaut syndrome is characterized by different types of seizures that typically begin in early childhood and may be associated with intellectual disability. Clobazam has been shown in controlled clinical trials to reduce drop (atonic) seizures in children with LGS, but there is evidence that it is effective for other seizure types as well. Clobazam is a 1,5-benzodiazepine that acts as a positive allosteric modulator of GABAA receptors. It is often used in combination with other drugs, including stiripentol, cannabidiol, and many others. Clobazam is extensively metabolized in the liver by cytochrome P450 (CYP) and non-CYP transformations. The major metabolite is N-desmethylclobazam (norclobazam), which has similar activity to clobazam on GABAA receptors and is an active antiseizure agent. During chronic treatment, levels of norclobazam are 8–20 times higher than those of the parent drug so that seizure protection during chronic therapy is mainly due to this metabolite. Norclobazam is principally metabolized by CYP2C19. Individuals who lack CYP2C19 activity (“CYP2C19 poor metabolizers”) have higher plasma levels of norclobazam and are at an increased risk of adverse effects. The FDA-approved drug label states that for patients known to be CYP2C19 poor metabolizers, the starting dose of clobazam should be 5 mg/day. Dose titration should proceed slowly according to weight, but to half the standard recommended doses, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21. [from Medical Genetics Summaries]

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]

Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; 601769) (Koren, 2006; Liberman and Marx, 2001). In the liver, vitamin D 25-hydroxylase (CYP2R1; 608713) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; 609506) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (Takeyama et al., 1997). Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (Liberman and Marx, 2001). Genetic Heterogeneity of Vitamin D-Dependent Rickets Vitamin D-dependent rickets type 1A (VDDR1A) is due to an enzymatic defect in synthesis of the active form of vitamin D caused by mutation in the CYP27B1 gene. VDDR1B (600081) is a form of rickets due to mutation in the gene encoding a vitamin D 25-hydroxylase (CYP2R1; 608713), another enzyme necessary for the synthesis of active vitamin D. Vitamin D-dependent rickets type 2A (VDDR2A; 277440) is caused by end-organ unresponsiveness of active vitamin D due to mutation in the gene encoding the vitamin D receptor (VDR; 601769). VDDR2B (600785) is an unusual form of end-organ unresponsiveness to active vitamin D due to an abnormal protein (see HNRNPC, 164020) that interferes with the function of the VDR. VDDR3 (619073) is a dominant form of VDDR caused by accelerated inactivation of vitamin D metabolites due to mutation in the CYP3A4 gene (124010). Other Forms of Hypophosphatemic Rickets For a discussion of other forms of hypophosphatemic rickets, see ADHR (193100). [from OMIM]

Dronabinol is the main psychoactive component in marijuana. Dronabinol is used in the treatment of chemotherapy-induced nausea and vomiting (CINV) among individuals who have not responded to conventional antiemetic therapy, and to treat anorexia associated with weight loss in individuals with acquired immunodeficiency syndrome (AIDS). Dronabinol is primarily metabolized by CYP2C9, which is responsible for the formation of the major active metabolite (11-hydroxy-delta-9-THC). Individuals who lack CYP2C9 activity (“CYP2C9 poor metabolizers”) have an increased exposure to dronabinol and an increased risk of side effects. Adverse events associated with dronabinol therapy include sedation, physical weakness, facial flushing, and palpitations.nThe FDA-approved drug label for dronabinol recommends monitoring for the increased adverse reactions that could potentially occur in individuals who are known to have genetic variants associated with diminished CYP2C9 function. The label states that published data indicates these individuals may have a 2- to 3-fold higher exposure to dronabinol. [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]