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]

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most commonly prescribed drugs to treat pain, fever and inflammation. The main therapeutic effect of NSAIDs occurs via blocking the production of prostaglandin that cause inflammation. Hepatic metabolism by cytochrome P450 isoforms CYP2C9, 1A2, and 3A4, and renal excretion are the principal routes of clearance of the majority of NSAIDs. Genetic variants in CYP2C9 (e.g., CYP2C9*2 and *3), along with other genetics and clinical factors, have been shown to affect systemic plasma concentrations of NSAIDs and potentially safety. Patients with CYP2C9 decreased or no function alleles may have elevated exposure and at increased risk for adverse effects. Guidelines regarding the use of pharmacogenomic tests in dosing for NSAIDs 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 a number of NSAIDs (celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam) based on CYP2C9 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]

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]

Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a metformin stimulus. [GOC:TermGenie] [from GO]

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]

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most commonly prescribed drugs to treat pain, fever and inflammation. The main therapeutic effect of NSAIDs occurs via blocking the production of prostaglandin that cause inflammation. Hepatic metabolism by cytochrome P450 isoforms CYP2C9, 1A2, and 3A4, and renal excretion are the principal routes of clearance of the majority of NSAIDs. Genetic variants in CYP2C9 (e.g., CYP2C9*2 and *3), along with other genetics and clinical factors, have been shown to affect systemic plasma concentrations of NSAIDs and potentially safety. Patients with CYP2C9 decreased or no function alleles may have elevated exposure and at increased risk for adverse effects. Guidelines regarding the use of pharmacogenomic tests in dosing for NSAIDs 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 a number of NSAIDs (celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam) based on CYP2C9 genotype. [from PharmGKB]