2016 Jun 8 [updated 2025 Jan 17]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

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 (1, 2).

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 (3). There is also a propensity for clozapine use to induce metabolic effects, resulting in substantial weight gain (1).

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 (4). Other CYP enzymes involved in clozapine metabolism include CYP2D6, CYP3A4, and CYP2C19 (5).

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 (Table 1) (1). However, the Dutch Pharmacogenetics Working Group (DPWG, Table 2) does not recommend dose alterations based on CYP2D6 genotype, though the gene-drug interaction is acknowledged (6). 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 (6). 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 (7, 8).

PMID:28520368 | Bookshelf:NBK367795

2012 Sep 20 [updated 2025 Jan 17]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Codeine is used to relieve mild to moderately severe pain, and it belongs to the drug class of opioid analgesics. Codeine has also been prescribed to prevent coughing, though the antitussive administration is most often in liquid formulations and in conjunction with other medications. (1, 2)

The hepatic CYP2D6 enzyme metabolizes a quarter of all prescribed drugs, including codeine. The CYP2D6 enzyme converts codeine into its active metabolite, morphine, which provides its analgesic effect. Consequently, pain relief may be inadequate in individuals who have 2 inactive copies of CYP2D6 (“poor metabolizers”, PMs), because of reduced morphine levels.

In contrast, individuals who have more than 2 normal-function copies of the CYP2D6 gene (“ultrarapid metabolizers”, UMs) are able to metabolize codeine to morphine more rapidly and more completely. As a result, even with therapeutic doses of codeine, these individuals may experience the symptoms of morphine overdose, which include extreme sleepiness, confusion, and shallow breathing, which in some instances can be fatal. Nursing mothers with ultrarapid CYP2D6 metabolism may also produce breast milk containing higher than expected levels of morphine that can lead to severe adverse events in their infants. (3)

The FDA-drug label for codeine states that even at labeled dosage regimens, individuals who are UMs may have life-threatening or fatal respiratory depression or experience signs of overdose (Table 1). The label also contains a boxed warning, which states that respiratory depression and death have occurred in children who received codeine following tonsillectomy, adenoidectomy, or both, and had evidence of being CYP2D6 UMs.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, another analgesic should be used to avoid the risk of severe toxicity with a “normal” dose of codeine. CPIC also recommends avoiding codeine in individuals identified as CYP2D6 PMs due to the possibility of lack of effect (Table 2). (4)

The Dutch Pharmacogenetics Working Group (DPWG) have published codeine dosing recommendations based on CYP2D6 genotype, and condition being treated (cough or pain), typical dosing, and additional risk factors, such as reduced kidney function or co-medication with CYP3A4 inhibitors. For UMs, the DPWG recommends an alternative to codeine for the treatment of pain (for example, oxycodone) (Table 3). (5)

PMID:28520350 | Bookshelf:NBK100662

2017 Mar 23 [updated 2025 Jan 6]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Imipramine is a tricyclic antidepressant (TCA) 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 for managing panic attacks, neuropathic pain, attention-deficit disorder, and childhood enuresis (bedwetting) (1).

Tricyclic antidepressants primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, increasing the concentration of these neurotransmitters in the synaptic cleft stimulating the neuron. Because tricyclics can also block different receptors (histamine H1, α1-adrenergic, and muscarinic receptors), side effects are common. Consequently, more selective serotonin reuptake inhibitors have largely replaced TCAs. However, TCAs still have an important role in treating specific types of depression and other conditions.

Imipramine is primarily metabolized via CYP2C19 to active metabolites, including desipramine, another TCA. Further metabolism is catalyzed by CYP2D6 to create inactive metabolites. Individuals who are “CYP2D6 ultrarapid metabolizers” (CYP2D6 UM) have more than 2 normal-function alleles (multiple copies), whereas individuals who are “CYP2C19 ultrarapid metabolizers” (CYP2C19 UM) have 2 increased-function alleles. Individuals who are CYP2D6 or CYP2C19 “poor metabolizers” (PM) have 2 no-function alleles for CYP2D6 or CYP2C19. Individuals who are CYP2D6 or CYP2C19 “intermediate metabolizers” (IM) have one no-function allele. Individuals with one normal-function and one increased-function allele for CYP2C19 are classified as “rapid metabolizers” (CYP2C19 RM).

The FDA-approved drug label for imipramine states that CYP2D6 PMs have higher-than-expected plasma concentrations of TCAs when given usual doses. The FDA recommendations include monitoring TCA plasma levels whenever a TCA is co-administered with another drug known to inhibit CYP2D6 (Table 1) (1).

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association has also issued dose-adjustment recommendations based on CYP2C19 and CYP2D6, as well (Table 2) (2). Individuals who are CYP2D6 IM should take 70% of the standard dose and be monitored for side effects and appropriate plasma levels of imipramine and desipramine. A genotype associated with CYP2D6 PM status warrants a decrease to 30% of the standard dose, with similar monitoring for adverse effects and plasma concentration to optimize dosing. The DPWG recommends a dose increase for CYP2D6 UM individuals, up to 1.7 times the standard dose if the potentially cardiotoxic hydroxy metabolites can be tolerated; otherwise, imipramine should be avoided. For CYP2C19 PMs, DPWG recommends taking 70% of the standard dose, along with close monitoring for side effects or plasma levels of imipramine and desipramine to determine an appropriate maintenance dose; alternatively, avoidance of imipramine is recommended (2). No dosing changes are recommended for CYP2C19 UM or IM individuals. When monitoring plasma levels of the active drug and metabolites, the combined levels of imipramine and desipramine should remain within 150–300 ng/mL; levels above 500 ng/mL are considered toxic (2).

In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) provided dosing recommendations for TCAs based on CYP2C19 and CYP2D6 genotype, either alone (Table 3) or in combination (Table 4). Amitriptyline and nortriptyline were used as model drugs for the guideline because most pharmacogenomic studies have focused on these 2 drugs. According to the CPIC guideline, because TCAs have comparable pharmacokinetic properties, the recommendations may be reasonably applied to other tricyclics, including imipramine (3).

For CYP2D6 UMs, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy and suggests considering an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends titrating the TCA to a higher target dose (compared to normal metabolizers [NM]) and using therapeutic drug monitoring (TDM) to guide dose adjustments. For CYP2D6 IMs, CPIC recommends a 25% reduction of the starting dose, while for CYP2D6 PMs, advises avoiding tricyclics due to the potential for side effects. If a TCA is still warranted for CYP2D6 PMs, CPIC recommends a 50% reduction in the starting dose with drug plasma concentration monitoring to avoid side effects. For gene-based dosing of TCAs for neuropathic pain, where the initial doses are lower, CPIC does not recommend dose modifications for PMs or IMs (either CYP2D6 or CYP2C19). For CYP2D6 UM individuals, CPIC optionally recommends considering an alternative medication due to a higher risk of therapeutic failure of TCAs for neuropathic pain (3).

For CYP2C19 UMs, CPIC recommends avoiding tertiary amines (for example, imipramine) due to the potential for a sub-optimal response and suggests considering an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 PMs, CPIC similarly recommends avoiding tertiary amines 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 PMs, CPIC recommends a 50% reduction of the starting dose while monitoring drug plasma concentrations to minimize side effects (3).

PMID:28520379 | Bookshelf:NBK425164

2024 Nov 13. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Valbenazine (marketed as Ingrezza in the US and Dysval in Japan) is a vesicular monoamine transporter 2 (VMAT2) inhibitor used in the treatment of tardive dyskinesia (TD) or Huntington disease (HD) chorea (1, 2). Valbenazine and its active metabolite inhibit the transporter protein that packages neurotransmitters into synaptic vesicles, reducing uncontrollable movements attributed to dopamine receptor hypersensitivity and other synaptic dysfunction. The active valbenazine metabolite is further metabolized into inactive compounds by cytochrome P450 (CYP450) family enzymes, including the CYP2D6 protein.

Individuals with no CYP2D6 enzymatic activity (poor metabolizers [PMs]) will have a higher exposure to valbenazine and its active metabolite, which can increase the risk of exposure-related adverse reactions (1). Therefore, the US FDA-approved label recommends that known CYP2D6 PMs take no more than 40 mg valbenazine daily. Individuals with other metabolizer phenotypes may take up to 80 mg daily, with dosing based on individual symptoms and tolerability (Table 1) (1). Notably, the FDA also advises the same lower dose for individuals taking a strong CYP2D6 inhibitor (1).

The FDA-approved label further cautions that individuals with HD are at increased risk for depression and suicidal ideation or behavior, particularly with VMAT2 inhibitor therapy (1). The recommended dosing in this population follows a slower titration time scale than for TD, with dose increases of 20 mg every 2 weeks until either efficacy is achieved, or the maximum tolerated dose is reached.

PMID:39565887 | Bookshelf:NBK609326

2017 Apr 4 [updated 2024 Oct 21]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Carisoprodol is a centrally acting muscle relaxant used to relieve acute back pain. Due to its potential for dependence and abuse, it should only be used for treatment periods of up to 2–3 weeks. Carisoprodolol is classified as a Schedule IV controlled substance, and overdose may result in central nervous system respiratory depression, seizures, or even death.

Carisoprodol is metabolized by the enzyme CYP2C19 into meprobamate, a sedative used for anxiety disorders. In individuals with low or absent CYP2C19 activity (termed “CYP2C19 poor metabolizers”), standard doses of carisoprodol can lead to a 4-fold increase in exposure to carisoprodol and a concurrent 50% decrease in meprobamate exposure compared to normal metabolizers. Approximately 3–5% of Caucasians and Africans, and 15–20% of Asians, are CYP2C19 poor metabolizers (1).

The FDA-approved drug label advises caution when prescribing carisoprodol to individuals with reduced CYP2C19 activity (Table 1) and when co-administering drugs that inhibit or induce CYP2C19 (1). The efficacy, safety, and pharmacokinetics of carisoprodol have not been established in pediatric individuals (under 16 years) or individuals over 65 years.(1). Decades of clinical use have not identified a risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes associated with carisoprodol (1).

PMID:28520382 | Bookshelf:NBK425390

2017 Apr 10 [updated 2024 Oct 15]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Prasugrel (also known as Efient) is a third-generation thienopyridine platelet inhibitor used in individuals with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prasugrel is prescribed to reduce thrombotic cardiovascular events, such as stent thrombosis, myocardial infarction, and stroke in these individuals. Along with other antiplatelet agents such as clopidogrel and ticagrelor, prasugrel inhibits platelet activation by irreversibly binding to the platelet receptor, P2RY12. (1)

Prasugrel is metabolized into its active metabolite primarily by CYP3A5 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. The FDA-approved label for prasugrel states that genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 genes do not significantly affect prasugrel’s pharmacokinetics, the generation of its active metabolite, or its inhibition of platelet aggregation in healthy subjects, individuals with stable atherosclerosis, or those with ACS (1).

Another commonly prescribed antiplatelet agent is the second-generation thienopyridine clopidogrel, which is bioactivated primarily by CYP2C19. As a result,, clopidogrel is less effective in individuals with decreased or non-function variant alleles of the CYP2C19 gene. In contrast, CYP2C19 variants do not decrease the effectiveness of prasugrel, which is a more potent antiplatelet agent compared to clopidogrel, though it carries a higher risk of bleeding (2, 3, 4, 5).

PMID:28520385 | Bookshelf:NBK425796

2023 May 2 [updated 2024 Aug 22]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Hydroxychloroquine, which is closely related to chloroquine, can be used for the prevention and treatment of some forms of malaria and rheumatic conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Malaria is an infection caused by the Plasmodium parasite, transmitted via mosquito bites. Hydroxychloroquine sulfate is indicated for the prevention and treatment of uncomplicated malaria due to sensitive strains of Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium knowlesi (P. knowlesi) by both the US Centers for Disease Control (CDC) and World Health Organization (WHO) (1, 2). Resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus hydroxychloroquine therapy is not recommended if the infection arose in a region with known resistance. Most P. falciparum infections are resistant to the 4-aminoquinolines (chloroquine and hydroxychloroquine), and as such these drugs are no longer used widely for these infections. Hydroxychloroquine must be co-administered with an 8-aminoquinoline compound for the radical cure of P. vivax or P. ovale infection to eliminate the hypnozoite forms of these parasites. (3) Additionally, hydroxychloroquine is indicated for the treatment of many rheumatoid conditions in adults, including chronic discoid lupus erythematosus, systemic lupus erythematosus, as well as acute and chronic rheumatoid arthritis. Hydroxychloroquine has also been used in an off-label capacity for the management of Sjögren syndrome (4).

Hydroxychloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. Among antimalarial medications, hydroxychloroquine is less likely than other medicines to cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals; however, the U.S. FDA-approved drug label states there is still a risk of acute hemolytic anemia (AHA) (Table 1) (3). In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of AHA for individuals with G6PD deficiency who take hydroxychloroquine (5). It should be noted that G6PD deficiency has a range of severity; CPIC advises caution for all medications when used by an individual with a severe G6PD deficiency with chronic non-spherocytic hemolytic anemia (CNSHA) (Table 2) (5). Regardless of G6PD phenotype, chronic use of hydroxychloroquine can cause irreversible retinal damage and regular visual exams are recommended by the FDA (3).

PMID:37184194 | Bookshelf:NBK591356

2015 Sep 10 [updated 2024 Aug 21]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Tramadol (brand names ConZip, Ultram, UltramER, Odolo) is an analgesic used to treat moderate to severe pain. It is used for a variety of pain conditions, including post-operative pain, cancer pain, and musculoskeletal pain. Tramadol is a centrally acting opioid analgesic with mu-opioid binding activity as well as weak inhibition of reuptake of norepinephrine and serotonin.

The CYP2D6 enzyme converts tramadol to the active metabolite, O-desmethyltramadol (M1), which has a significantly higher affinity for the mu-opioid receptor than tramadol. The M1 metabolite is up to 6 times more potent than tramadol in producing analgesia.

Individuals who have reduced CYP2D6 activity are known as “intermediate metabolizers” and those with absent CYP2D6 activity are known as “poor metabolizers.” The standard recommended doses of tramadol may not provide adequate pain relief in these individuals because of reduced levels of M1. Whereas in individuals who have increased CYP2D6 activity (“ultrarapid metabolizers”), standard doses of tramadol may result in a higher risk of adverse events because of increased exposure to M1.

The 2021 FDA-approved drug label warns that individuals who are ultrarapid metabolizers (UMs) should not use tramadol because of the risk of life-threatening respiratory depression and signs of opiate overdose (for example, extreme sleepiness, confusion, or shallow breathing) (Table 1) (1).

The prevalence of CYP2D6 UM varies but is thought to be present in approximately 1–10% of Caucasians (European, North American), 3–4% of Blacks (African Americans), and 1–2% of East Asians (Chinese, Japanese, Korean). The frequency of UM phenotype has been reported to be even higher in some groups, including Ashkenazi Jews and regional populations in the Middle East.

Furthermore, tramadol is not recommended in nursing mothers due to the potential exposure to high levels of M1 causing life-threatening respiratory depression, if the mother is a UM. At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an UM of codeine, which—similar to tramadol—is activated by CYP2D6 metabolism.

Tramadol is contraindicated for all children younger than age 12 and for all individuals under the age of 18 when being used for post-operative analgesia following tonsillectomy or adenoidectomy, or both. The label warns that life-threatening respiratory depression and death have occurred in children who received tramadol, and in at least one case, the child was an UM of tramadol.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that for an individual identified as a CYP2D6 UM, a different non-CYP2D6 dependent analgesic should be used to avoid the risk of severe toxicity with standard dosing of tramadol. The CPIC also recommends avoiding tramadol in individuals identified as CYP2D6 poor metabolizers (PMs) due to the possibility of lack of effect (Table 2) (2).

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) provides dosing recommendations for tramadol based on CYP2D6 genotype (Table 3). The DPWG states it is not possible to calculate a dose adjustment for tramadol, because when the ratio of tramadol and M1 is altered, the nature and total analgesic effect of tramadol also changes. For CYP2D6 UM, DPWG recommends selecting an alternative drug to tramadol - but not codeine, which is also metabolized by CYP2D6. Alternative drugs include morphine (not metabolized by CYP2D6) and oxycodone (which is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in clinical practice). For CYP2D6 poor (PM) and intermediate metabolizers (IM), DPWG recommends increasing the dose of tramadol, and if this does not have the desired effect, selecting an alternative drug (not codeine) (Table 3) (3).

PMID:28520365 | Bookshelf:NBK315950

2024 Aug 12. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Lecanemab, brand name Leqembi, is a monoclonal antibody that targets amyloid beta (Aβ) aggregates for the treatment of Alzheimer disease (AD) (1). It is approved by the US Food and Drug Administration (FDA) for individuals with mild cognitive impairment (MCI) or mild dementia stage AD with confirmed amyloid pathology (1). Tests to confirm Aβ pathology in the clinical trials included positron emission tomography (PET) or cerebrospinal fluid (CSF) measurement of the Aβ42/Total Tau ratio (2). This disease-modifying medication is based on the amyloid cascade hypothesis, which suggests Aβ aggregates are a key driver in AD pathogenesis and that the removal of Aβ aggregates should slow cognitive decline.

Lecanemab is associated with amyloid-related imaging abnormalities (ARIA) due to edema (ARIA-E) or hemorrhage (ARIA-H) from blood vessels in the brain (3, 4). Individuals who have one or 2 copies of the AD risk-associated apolipoprotein E (APOE) ε4 (NM_000041.4:c.388T>C) allele have an increased risk of ARIA-E or -H (1) (Table 1). These individuals require additional monitoring during the first year of treatment (5). The FDA-approved label reports that concomitant antithrombotic medication (aspirin, antiplatelet, or anticoagulant) with lecanemab therapy resulted in intracerebral hemorrhage in 2.5% of individuals during clinical trials (1).

The appropriate use recommendations from the Alzheimer’s Disease and Related Disorders Therapeutics Work Group state that individuals requiring anticoagulants should not be treated with lecanemab until additional data regarding this interaction are available (5). Both the FDA-approved label and Alzheimer’s Disease and Related Disorders Therapeutics Work group encourage clinicians to consider participation in a registry for AD treatment to gather additional real-world data on lecanemab therapy (1, 5).

PMID:39141762 | Bookshelf:NBK605938

2024 Jul 31. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.

ABSTRACT

Macular degeneration is an age-related disease of the retina marked by progressive loss of central visual acuity. It is the major cause of visual loss above the age of 60 and risk factors include family history, smoking, being overweight or obese, and hypertension. Age-related macular degeneration occurs in two forms: “dry” and “wet”.

Dry macular degeneration accounts for 80% to 90% of cases and is caused by thinning of the retina, retinal cell loss, and subretinal accumulation of abnormal protein in clumps (drusen). In advanced forms there is patchy atrophy, referred to as geographic atrophy. Recently, agents have been developed for treatment of age-related dry macular degeneration with geographic atrophy. Approved agents include drugs that inhibit complement activation (avacincaptad pegol and pegcetacoplan). The agents are given by intravitreal injections every 1 to 2 months.

Wet macular degeneration accounts for 10% to 20% of cases and is due to neovascularization in the subretinal space with abnormal and leaky blood vessels. The vascularization is dependent, at least in part, on action of vascular endothelial growth factor (VEGF). Wet macular degeneration is treatable with agents that specifically target VEGF which, when given as intravitreal injections, slow the progression of (but do not cure) the neovascularization. These include monoclonal antibodies to VEGF (bevacizumab, brolucizumab, ranibizumab, faricimab), aptamers (small oligonucleotides that bind to VEGF: pegaptanib), and fusion VEGF receptor proteins that act as a decoy of the circulating growth factor (aflibercept). The agents are given as intravitreal injections every 4 to 8 weeks.

Most adverse events of these agents are ocular and relate to their local injection. Systemic exposure is limited and ex-ocular adverse events are rare. Some of the agents have been implicated in cardiovascular or cerebrovascular thromboembolic events, but these are uncommon. None of the drugs for macular degeneration have been implicated in causing hepatotoxicity, either serum enzyme elevations during treatment or clinically apparent liver injury, at least when administered by intravitreal injection. The lack of hepatotoxicity is probably due largely to the lack of significant systemic absorption and exposure. When given intravenously as therapy of neoplastic conditions, several have been linked to rare instances of liver injury.

PMID:31643677 | Bookshelf:NBK548356

2016 Sep 15 [updated 2024 Jun 28]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

NO ABSTRACT

PMID:28520371 | Bookshelf:NBK385154

2024 Jun 2. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.

ABSTRACT

Metamizole, also known as dipyrone, is an oral analgesic that is not available in the United States but is available over-the-counter in many countries of the world. Therapy with metamizole has been associated with rare severe bone marrow and liver adverse events including agranulocytosis, acute hepatitis, and acute liver failure.

PMID:38861630 | Bookshelf:NBK604194

2017 Aug 15 [updated 2023 Dec 4]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Dabrafenib (brand name Tafinlar) is a kinase inhibitor used in the treatment of individuals with unresectable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic anaplastic thyroid cancer (ATC), pediatric low-grade glioma (LGG), and other unresectable or metastatic solid tumors with specific BRAF variants. Dabrafenib can be used as a single agent to treat melanoma with the BRAF valine 600 to glutamic acid (V600E) variant or in combination with the MEK inhibitor trametinib to treat multiple tumor types with BRAF V600E or V600K variants. (1)

The BRAF protein is an intracellular kinase in the mitogen-activated protein kinases (MAPK) pathway. Functionally, BRAF regulates essential cell processes such as cell growth, division, differentiation, and apoptosis. The gene BRAF is also a proto-oncogene—when mutated, it transforms normal cells into cancerous cells.

Variation in the kinase domain of BRAF is associated with various cancers. The most common BRAF variant, V600E, constitutively activates the kinase and causes cell proliferation in the absence of growth factors that would usually be needed. The V600E variant is detected in approximately 50% of melanomas, 25% of ATC, 2% of NSCLC, and 20% of pediatric LGGs (2, 3, 4, 5, 6, 7, 8).

The FDA-approved label for dabrafenib states that the presence of BRAF mutation in tumor specimens (V600E for dabrafenib monotherapy; V600E or V600K for dabrafenib plus trametinib) should be confirmed using an FDA-approved test before starting treatment with dabrafenib. Dabrafenib is not indicated for the treatment of individuals with wild-type BRAF tumors, or the treatment of colorectal cancer due to intrinsic resistance to BRAF inhibitor monotherapy. (1)

The label also states that individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be monitored for signs of hemolytic anemia while taking dabrafenib (1). However, it is important to note that an independent literature review by the Clinical Pharmacogenetics Implementation Consortium found no publications to support or refute this risk and thus issued no guidance for G6PD deficiency and dabrafenib therapy (9).

PMID:28809523 | Bookshelf:NBK447415

2023 Oct 17. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Atazanavir is indicated for managing human immunodeficiency virus (HIV) infection as part of a multi-drug regimen (1). While it was once widely recommended as a first-line therapy, it is now primarily suggested as a second-line therapeutic option due to potential adverse effects leading to discontinuation of therapy (2, 3). Atazanavir can cause hyperbilirubinemia (not associated with liver injury) leading to jaundice, which is a common cause of drug discontinuation. Individuals with 2 decreased-function alleles for UGT1A1 are most likely to experience jaundice leading to atazanavir discontinuation, although this can occur despite the individual having a reference UGT1A1 genotype (4). The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that when an individual is a known UGT1A1 poor metabolizer, an alternative therapy should be considered particularly when jaundice is of concern to the individual (Table 1) (4). The US Food and Drug Administration (FDA) approved drug label states that certain comedications that depend upon UGT1A1 or the cytochrome P450 family member CYP3A are contraindications for atazanavir therapy due to the potential for elevated plasma concentrations of these comedications (1).

PMID:37851848 | Bookshelf:NBK596252

2023 Aug 9. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Siponimod (brand name Mayzent) is a sphingosine-1-phosphate (S1P) receptor modulator used in the treatment and management of relapsing forms of multiple sclerosis (MS) in adults. It works by targeting lymphocytes to decrease the number of circulating cells that are associated with MS symptomatic attacks and disease progression and may also have a direct neuroprotective impact. Siponimod strongly binds to the S1P type 1 and type 5 receptors that are abundantly expressed on lymphocytes and multiple other cell types in the central nervous system (CNS). Off-target interactions and effects on cardiac cells may occur, also. The use of a dose titration schedule is recommended to decrease the risk of bradycardia (see Table 1, Table 2) (1, 2). This medication is approved for multiple forms of relapsing MS (RMS) in the United States (1) and for active, secondary progressive disease in Europe and Canada (2, 3).

Siponimod is metabolized by members of the cytochrome P450 family, specifically CYP2C9 and, to a lesser extent CYP3A4. The CYP2C9 gene is polymorphic and activity scores are used to categorize diplotype into phenotype. Decreased CYP2C9 metabolic activity is associated with increased exposure to siponimod and increased risk of adverse effects. Therefore, individuals with the CYP2C9*3/*3 diplotype (activity score = 0) are contraindicated from taking siponimod (1, 2). Individuals with one copy of the no-function *3 allele (diplotype with activity scores of 0.5 or 1.0) are advised to take half the standard maintenance dose (1, 2). Consideration of genotype and activity score is essential for CYP2C9-based siponimod dosing because labeled dose recommendations are not categorized by phenotype. In the US, there is a modified titration schedule for individuals with a CYP2C9*3 allele (Table 1)(1); however, the European prescribing guidelines do not modify the titration schedule for individuals with a single copy of the CYP2C9*3 allele (heterozygous for CYP2C9*3) (Table 2) (2). The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy similarly recommends a 50% reduced maintenance dosage for intermediate metabolizers (IM) (Table 3) (4). It should be noted that dose recommendations in the Siponimod package label are limited to diplotypes consisting of only CYP2C9 *1,*2, and *3 alleles due to lack of clinical data on the impact of other decreased or no-function alleles(1), while other medication and testing guidelines also consider*5, *6, *8, and *11 (5, 6).

PMID:37561888 | Bookshelf:NBK593688

2023 Jul 20. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Belinostat (brand name Beleodaq) is a histone deacetylase (HDAC) inhibitor, approved for the treatment of relapsed or refractory peripheral T-cell lymphomas (PTCLs) (1). Belinostat targets 3 classes of HDACs (I, II and IV), resulting in higher levels of acetylation of both histone and non-histone proteins, thus reversing the changes in protein acetylation that are frequently disrupted during oncogenesis. Belinostat is administered as an infusion at a rate of 1000 mg/m2 for 30 minutes on days 1–5 of a 21-day cycle (1).

Belinostat has a relatively short half-life and is primarily metabolized by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1)-mediated glucuronidation, with minor contributions from other UGT and cytochrome P450 (CYP) enzymes (1, 2). Genetic variation at the UGT1A1 locus can result in decreased enzyme activity and thus increased exposure to belinostat. The US Food and Drug Administration (FDA)-approved drug label recommends a 25% decrease in dose for individuals who are known to be homozygous for the UGT1A1*28 reduced function allele (Table 1) (1). Additional indications for dose reduction include grade 3 or 4 adverse reactions or significant decrease in neutrophil or platelet counts following belinostat administration (1). Some studies have suggested that other variant alleles may also lead to increased belinostat exposure, such as UGT1A1*60; however, no specific recommendations for dose reduction have been made for these alleles by either the FDA or other professional pharmacogenetic consortia. Belinostat should not be administered with other medications that can inhibit UGT1A1 function (1), such as nilotinib, ketoconazole, or ripretinib.

PMID:37487012 | Bookshelf:NBK593302

2023 Jul 6. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

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 (1, 2). 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 (1, 2). According to the FDA-approved drug label, individuals with severe G6PD deficiency should not take primaquine (Table 1) (1).

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 (Table 2) (2). 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 (Table 3) (3).

Primaquine is contraindicated during pregnancy and is not recommended for breastfeeding individuals when the G6PD status of the baby is unknown (1, 2). 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. (1)

PMID:37428853 | Bookshelf:NBK592855

2023 May 16. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Chloroquine is used for the treatment of uncomplicated malaria and extra-intestinal amebiasis. Malaria is caused by infection of Plasmodium parasites. Chloroquine is active against the erythrocytic forms of susceptible strains of Plasmodium falciparum (P. falciparum), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium Vivax (P. vivax). Chloroquine is not active against the gametocytes and the exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites. Additionally, resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus chloroquine therapy is not indicated if the infection arose in a region with known resistance. Chloroquine is used in first-line treatment of P. vivax malaria with primaquine. Studies have indicated chloroquine is effective against the trophozoites of Entamoeba histolytica (E. histolytica), which causes amebic dysentery, or amebiasis. (1) Chloroquine also has off-label uses for treatment of rheumatic diseases and has been investigated as a potential antiviral therapy as well as an adjuvant chemotherapy for several types of cancer. (2, 3, 4, 5)

Chloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. This change in pH can impair the action of enzymes responsible for the formation of hemozoin by the parasite from ingestion of the host’s hemoglobin; this reaction occurs in the parasitic vacuole (6). Thus, chloroquine targets the blood-stage of the malaria parasites but cannot eliminate dormant hypnozoites and must be administered with a drug that targets the dormant parasitic form (1). Chloroquine, developed in the 1940s, has been superseded as the first-line recommended antimalarial therapy by both the US Centers for Disease Control (CDC) and World Health Organization (WHO), with the exceptions of during the first trimester of pregnancy or for malarial prophylaxis of a pregnant individual who is also deficient for glucose-6-phosphate dehydrogenase (G6PD) (7, 8). Among antimalarial medications, chloroquine is less likely than other medicines to cause hemolysis in G6PD-deficient individuals; however, the FDA-approved drug label states there is still a risk of hemolysis (Table 1) (1). In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of acute hemolytic anemia for individuals with G6PD deficiency who take hydroxychloroquine or chloroquine (9) (Table 2). It should be noted that G6PD deficiency has a range of severity; CPIC advises caution for all medications when used by an individual with a severe G6PD deficiency with chronic non-spherocytic hemolytic anemia (CNSHA).

PMID:37196138 | Bookshelf:NBK591833

2023 Jan 28. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.

ABSTRACT

Guarana is an extract of roasted and pulverized seeds of the plant Paullinia cupana which is indigenous to the Amazon Basin and whose major active components are caffeine and other xanthine alkaloids such as theophylline and theobromine. Guarana has been used as a stimulant and tonic to treat fatigue, decrease hunger and thirst and for headaches and dysmenorrhea. In conventional doses, guarana has few side effects and has not been linked to episodes of liver injury or jaundice.

PMID:36753599 | Bookshelf:NBK589113

2012 Mar 8 [updated 2022 Dec 1]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.

ABSTRACT

Clopidogrel (brand name Plavix) is an antiplatelet medicine that reduces the risk of myocardial infarction (MI) and stroke in individuals with acute coronary syndrome (ACS), and in individuals with atherosclerotic vascular disease (indicated by a recent MI or stroke, or established peripheral arterial disease) (1). Clopidogrel is also indicated in combination with aspirin for individuals undergoing percutaneous coronary interventions (PCI), including stent placement.

The effectiveness of clopidogrel depends on its conversion to an active metabolite, which is accomplished by the cytochrome P450 2C19 (CYP2C19) enzyme. Individuals who have 2 loss-of-function copies of the CYP2C19 gene are classified as CYP2C19 poor metabolizers (PM). Individuals with a CYP2C19 PM phenotype have significantly reduced enzyme activity and cannot activate clopidogrel via CYP2C19, which means the drug will have a reduced antiplatelet effect. Approximately 2% of Caucasians, 4% of African Americans, 14% of Chinese, and 57% of Oceanians are CYP2C19 PMs (2). The effectiveness of clopidogrel is also reduced in individuals who are CYP2C19 intermediate metabolizers (IM). These individuals have one loss-of-function copy of CYP2C19, with either one normal function copy or one increased function copy. The frequency of the IM phenotype is more than 45% in individuals of East Asian descent, more than 40% in individuals of Central or South Asian descent, 36% in the Oceanian population, approximately 30% in individuals of African descent, 20–26% in individuals of American, European, or Near Eastern descent, and just under 20% in individuals of Latino descent (2).

The 2022 FDA-approved drug label for clopidogrel includes a boxed warning on the diminished antiplatelet effect of clopidogrel in CYP2C19 PMs (Table 1). The warning states that tests are available to identify individuals who are CYP2C19 PMs, and to consider the use of another platelet P2Y12 (purinergic receptor P2Y, G-protein coupled 12) inhibitor in individuals identified as CYP2C19 PMs.

The 2022 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for clopidogrel recommends that for individuals with ACS or non-ACS indications who are undergoing PCI, being treated for peripheral arterial disease (PAD), or stable coronary artery disease following MI, an alternative antiplatelet therapy (for example, prasugrel or ticagrelor) should be considered for CYP2C19 PMs if there is no contraindication (Table 2) (3). Similarly, CPIC strongly recommends that CYP2C19 IMs should avoid clopidogrel for ACS or PCI but makes no recommendations for other cardiovascular indications (Table 2). For neurovascular indications, CPIC recommends avoidance of clopidogrel for CYP2C19 PMs and consideration of alternative medications for both IMs and PMs if not contraindicated (Table 3) (3).

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have also made antiplatelet therapy recommendations based on CYP2C19 genotype. For individuals with ACS who undergo PCI, they recommend an alternative antiplatelet agent in PMs, and for IMs they recommend choosing an alternative antiplatelet agent or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose (Table 4) (4).

PMID:28520346 | Bookshelf:NBK84114