MedGen

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]

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]

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]

Esomeprazole (brand name Nexium) is a proton pump inhibitor (PPI) used to treat gastroesophageal reflux disease (GERD) and to reduce the risk of gastric ulcers associated with nonsteroidal anti-inflammatory drug NSAID use. Esomeprazole is also used in the treatment of hypersecretory conditions, such as Zollinger-Ellison syndrome, and in combination with antibiotics to eradicate Helicobacter pylori (H. pylori) infection. Esomeprazole reduces the acidity (raises the pH) in the stomach by inhibiting the secretion of gastric acid. The level of esomeprazole an individual is exposed to is influenced by several factors, such as the dose used and how quickly the drug is metabolized and inactivated. Esomeprazole is primarily metabolized by the CYP2C19 enzyme. Individuals with increased CYP2C19 enzyme activity (“CYP2C19 ultrarapid metabolizers”) may have an insufficient response to standard doses of esomeprazole, because the drug is inactivated at a faster rate. In contrast, individuals who have reduced or absent CYP2C19 enzyme activity (i.e., CYP2C19 intermediate and poor metabolizers) have a greater exposure to esomeprazole. The 2018 FDA-approved drug label for esomeprazole states that 3% of Caucasians, and 15–20% of Asians are CYP2C19 poor metabolizers, and that poor metabolizers have approximately twice the level of exposure to esomeprazole, compared with CYP2C19 normal metabolizers. However, the drug label does not include dosing recommendations for CYP2C19 poor metabolizers. Esomeprazole recommendations have been published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), which indicates that no change in dosing is recommended for CYP2C19 poor, intermediate, or ultrarapid metabolizers. The DPWG states that although genetic variation in CYP2C19 influences the plasma concentration of esomeprazole, there is insufficient evidence to support an effect on treatment outcomes or side effects. [from Medical Genetics Summaries]

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]

Voriconazole is a triazole antifungal agent active against a variety of fungi and molds. While it is generally well-tolerated and effective, it has a narrow therapeutic window making it difficult to dose correctly. CYP2C19 is the primary enzyme responsible for the metabolism of the drug, and variations within the CYP2C19 gene may affect voriconazole exposure. CYP2C19 ultrarapid and rapid metabolizers may have increased metabolism of the drug, resulting in a reduced likelihood of attaining therapeutic voriconazole concentrations, while poor metabolizers may have decreased metabolism of the drug, resulting in an increased likelihood for adverse effects. Therapeutic guidelines for voriconazole based on CYP2C19 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]

Clopidogrel is a thienopyridine antiplatelet agent that prevents platelet activation and aggregation by irreversibly inhibiting the P2Y12 ADP receptors. As a prodrug, clopidogrel requires hepatic biotransformation to form an active metabolite. This conversion is composed of two sequential oxidative steps, which involve cytochrome P450-2C19 (CYP2C19) and other enzymes. Genetic variants in CYP2C19, along with other genetic and non-genetic factors, are known to influence variability in clopidogrel response. Specific CYP2C19 variants impair formation of active clopidogrel metabolites, which results in reduced platelet inhibition. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience an increased risk for major adverse cardiovascular and cerebrovascular events. Therapeutic recommendations for clopidogrel based on an individual’s CYP2C19 genotype have been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the 2022 guideline update includes new recommendations for CYP2C19 genotype-guided antiplatelet therapy. [from PharmGKB]