[Pharmacogenomics study of 620 whole-exome sequencing: focusing on aspirin application].

Zhonghua Er Ke Za Zhi. 2016 May;54(5):332-6

Authors: Yang L, Lu YL, Wang HJ, Zhou WH

Abstract
OBJECTIVE: To investigate the allele frequencies of aspirin-response-related variants in different population.
METHOD: The allele frequencies of reported clinically significant aspirin-response-related variants were evaluated based on 620 whole exome sequencing (WES) data collected from 2013 to 2016 in Children's Hospital of Fudan University.Then the local allele frequencies were compared with 1 000 Genomes project database, and χ(2) test was used.
RESULT: Thirty-eight aspirin-response-related variants that had clinical significance had been detected in the 620 WES data.Ten (26%) of them were related with drug efficacy while 28 (74%) were related with toxicity or adverse drug reaction (ADR). These variants were distributed in 33 genes.There were 23 aspirin-related variants further analysised, and the frequency of 7 (rs1050891, rs6065, rs7862221, rs1065776, rs3818822, rs3775291 and rs1126643) had no significant difference compared with frequency of European and East Asian population of 1 000 Genome project (P>0.01 for both), 10 (rs2228079, rs1613662, rs4523, rs28360521, rs1131882, rs1047626, rs3856806, rs2768759, rs7572857 and rs1126510) of them had no significant difference compared with East Asian but were significantly different from European population, 1 (rs2075797) had no significant difference compared with frequency of European and different with frequency of East Asian, and 5 variants(rs10279545, rs730012, rs16851030, rs1353411, rs1800469)were different from frequency of both East Asian(0.019, 0.058, 0.167, 0.452, 0.340 vs. 0.100, 0.151, 0.396, 0.568, 0.453, χ(2)=21.798, 20.400, 67.543, 16.531, 15.807, P all<0.01) and European population(0.531, 0.312, 0.037, 0.179, 0.688, χ(2)=325.799, 92.877, 144.811, 156.471, 174.533, P all<0.01).
CONCLUSION: Most variants that have clinical significance in aspirin response are related with drug efficacy or drug toxicity or ADR, indicating the urgency of variants screen in clinical practice.Significant population-specificity is detected in local 620 WES data in aspirin-response-related variants.

PMID: 27143073 [PubMed - in process]

Invasive Aspergillus infection requiring lobectomy in a CYP2C19 rapid metabolizer with subtherapeutic voriconazole concentrations.

Pharmacogenomics. 2016 May 4;

Authors: Hicks JK, Gonzalez BE, Zembillas AS, Kusick K, Murthy S, Raja S, Gordon SM, Hanna R

Abstract
Individuals who carry the CYP2C19*17 gain-of-function allele have lower voriconazole exposure and are therefore at risk of failing therapy. Utilizing CYP2C19 genotype to optimize voriconazole dosage may be a cost-effective method of improving treatment outcomes. However, there are limited data describing what initial voriconazole dosage should be used in those with increased CYP2C19 metabolic capacity. Herein, we present a case report of a pediatric CYP2C19 rapid metabolizer (i.e., CYP2C19*1/*17) requiring a voriconazole dosage of 14 mg/kg twice daily (usual pediatric dosage ranges from 7 to 9 mg/kg twice daily). This case report supports the clinical utility of using CYP2C19 genotype to guide voriconazole dosing, and provides data for establishing an initial voriconazole dose in pediatric CYP2C19 rapid metabolizers.

PMID: 27143031 [PubMed - as supplied by publisher]

Differences in genetic variants in lopinavir disposition among HIV-infected Bantu Africans.

Pharmacogenomics. 2016 May 4;

Authors: Mpeta B, Kampira E, Castel S, Mpye KL, Soko ND, Wiesner L, Smith P, Skelton M, Lacerda M, Dandara C

Abstract
INTRODUCTION: Variability in lopinavir (LPV) plasma concentration among patients could be due to genetic polymorphisms. This study set to evaluate significance of variants in CYP3A4/5, SLCO1B1 and ABCC2 on LPV plasma concentration among African HIV-positive patients.
MATERIALS & METHODS: Eighty-six HIV-positive participants on ritonavir (LPV/r) were genetically characterized and LPV plasma concentration determined.
RESULTS & DISCUSSION: LPV plasma concentrations differed >188-fold (range 0.0206-38.6 µg/ml). Both CYP3A4*22 and SLCO1B1 rs4149056G (c.521C) were not observed in this cohort. CYP3A4*1B, CYP3A5*3, CYP3A5*6 and ABCC2 c.1249G>A which have been associated with LPV plasma concentration, showed no significant association.
CONCLUSION: These findings highlight the need to include African groups in genomics research to identify variants of pharmacogenomics significance.

PMID: 27142945 [PubMed - as supplied by publisher]

Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine.

Paediatr Drugs. 2016 May 3;

Authors: Maagdenberg H, Vijverberg SJ, Bierings MB, Carleton BC, Arets HG, de Boer A, Maitland-van der Zee AH

Abstract
It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting β2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting β2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.

PMID: 27142473 [PubMed - as supplied by publisher]

Identification of miR-34a-target interactions by a combined network based and experimental approach.

Oncotarget. 2016 Apr 29;

Authors: Hart M, Rheinheimer S, Leidinger P, Backes C, Menegatti J, Fehlmann T, Grässer F, Keller A, Meese E

Abstract
Circulating miRNAs have been associated with numerous human diseases. The lack of understanding the functional roles of blood-born miRNAs limits, however, largely their value as disease marker. In a systems biology analysis we identified miR-34a as strongly associated with pathogenesis. Genome-wide analysis of miRNAs in blood cell fractions highlighted miR-34a as most significantly up-regulated in CD3+ cells of lung cancer patients. By our in silico analysis members of the protein kinase C family (PKC) were indicated as miR-34a target genes. Using a luciferase assay, we confirmed binding of miR-34a-5p to target sequences within the 3'UTRs of five PKC family members. To verify the biological effect, we transfected HEK 293T and Jurkat cells with miR-34a-5p causing reduced endogenous protein levels of PKC isozymes. By combining bioinformatics approaches with experimental validation, we demonstrate that one of the most relevant disease associated miRNAs has the ability to control the expression of a gene family.

PMID: 27144431 [PubMed - as supplied by publisher]

Spatial Cross-Talk Between Oxidative Stress and DNA Replication in Human Fibroblasts.

J Proteome Res. 2016 May 4;

Authors: Radulovic M, Baqader NO, Stoeber K, Godovac-Zimmermann J

Abstract
MS-based proteomics has been applied to a differential network analysis of the nuclear-cytoplasmic subcellular distribution of proteins between cell cycle arrest: (a) at the origin activation checkpoint for DNA replication, or (b) in response to oxidative stress. Significant changes were identified for 401 proteins. Cellular response combines changes in trafficking and in total abundance to vary the local compartmental abundances that are the basis of cellular response. Appreciable changes for both perturbations were observed for 245 proteins, but cross-talk between oxidative stress and DNA replication is dominated by 49 proteins that show strong changes for both. Many nuclear processes are influenced by a spatial switch involving the proteins {KPNA2, KPNB1, PCNA, PTMA, SET} and heme/iron proteins HMOX1 and FTH1. Dynamic spatial distribution data is presented for proteins involved in caveolae, extracellular matrix remodelling, TGFβ signalling, IGF pathways, emerin complexes, mitochondrial protein import complexes, spliceosomes, proteasomes, etc. The data indicates that for spatially heterogeneous cells, cross-compartmental communication is integral to their systems biology, that coordinated spatial redistribution for crucial protein networks underlies many functional changes, and that information on dynamic spatial redistribution of proteins is essential to obtain comprehensive pictures of cellular function. We describe how spatial data of the type presented here can provide priorities for further investigation of crucial features of high-level spatial coordination across cells. We suggest that the present data is related to increasing indications that much of subcellular protein transport is constitutive and that perturbation of these constitutive transport processes may be related to cancer and other diseases. A quantitative, spatially resolved nucleus-cytoplasm interaction network is provided for further investigations.

PMID: 27142241 [PubMed - as supplied by publisher]

2017 Apr 4 [updated 2025 Apr 14]. 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

Propafenone is an antiarrhythmic medication that belongs to class IC of antiarrhythmic agents. It acts on cardiac sodium channels to inhibit action potentials. In adults, it is used to prevent the reoccurrence of episodic atrial or ventricular fibrillation in individuals without underlying structural heart disease (propafenone may provoke proarrhythmic events in individuals with structural heart disease) It is also used to treat life-threatening ventricular arrhythmias. In pediatric individuals, propafenone can prevent and abort supraventricular tachycardias, most commonly orthodromic reciprocating tachycardia, or treat ventricular arrhythmias.

Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 enzymes. Approximately 6% of Caucasians in the United States of America are classified as a CYP2D6 poor metabolizer (PM) suggesting they may be at risk for increased drug levels (1). Medications that inhibit CYP2D6, CYP3A4, and CYP1A2 enzymes may also increase propafenone levels. Ongoing investigation aims to better understand the relationship between metabolizer status, propafenone drug levels, and adverse events, as these factors may not have a linear relationship.

A guideline from The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association provides dosing recommendations for propafenone based on CYP2D6 genotype. For CYP2D6 PMs, the guideline recommends reducing the initial dose of propafenone to 30%, electrocardiogram (ECG) monitoring, and monitoring plasma concentrations. For intermediate and ultrarapid metabolizers (UMs), the guideline states there is insufficient data to allow for a calculation of dose adjustment. Instead, it recommends adjusting the dose in response to plasma concentration, monitoring with ECG, being alert to side effects or reduced efficacy, or selecting an alternative drug (namely, one that is less dependent on CYP2D6 metabolism such as sotalol, disopyramide, quinidine, or amiodarone) (2, 3) (Table 1).

The US FDA-approved drug label for propafenone does not recommend an altered dosing regimen based on CYP2D6 metabolizer status. However, the label cautions against the simultaneous use of propafenone with both a CYP2D6 inhibitor and a CYP3A4 inhibitor due to the possibility of propafenone’s proarrhythmic effect and other cardiac and systemic adverse events (1) (Table 2). The label also states that the combination of CYP3A4 inhibition and CYP2D6 deficiency in propafenone users is potentially hazardous and the Table of Pharmacogenetic Associations states “ avoid propafenone use in PMs who are taking a CYP3A4 inhibitor” (1, 4).

The Health Canada-approved drug monograph similarly advises that individuals who are genetically determined “slow metabolizers” of propafenone (due to CYP2D6 variants leading to enzymatic deficiency) will experience higher plasma concentrations, which may result in clinically evident beta-blockade (5).

PMID:28520383 | Bookshelf:NBK425391

2017 Apr 4 [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

Metoprolol is a beta-blocker indicated for the treatment of various cardiovascular diseases, including hypertension, arrhythmias, angina, myocardial infarction, and heart failure (HF). Metoprolol selectively blocks beta1-adrenoreceptors, which are expressed predominantly in cardiac tissue. The primary therapeutic effect resulting from the blockade of these receptors is a reduction in heart rate and a decrease in the force of heart contractions.

Metoprolol is metabolized extensively by the hepatic CYP2D6 enzyme. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are known as “CYP2D6 poor metabolizers (PM).” In addition, several drugs inhibit CYP2D6 activity, such as bupropion, quinidine, fluoxetine, paroxetine, and propafenone.

The FDA-approved drug label for metoprolol states that CYP2D6 PM and normal metabolizers (NM) who concomitantly take drugs that inhibit CYP2D6 will have increased metoprolol blood levels, decreasing metoprolol’s cardioselectivity; co-medication with CYP2D6 inhibitors warrants close monitoring (1). (Table 1) Beta-blockers, such as metoprolol, have been demonstrated in several large clinical trials to be safe and effective for the treatment of individuals with cardiovascular disease. As a mainstay of therapy associated with improvements in quality of life, hospitalization rates, and survival (2, 3), clinical care pathways that might lead to the underutilization of beta-blockers require scrutiny. It is common clinical practice to adjust the dose of metoprolol according to individual heart rate until either the target or maximum tolerated dose is reached. The FDA does not specifically comment on the role of genetic testing for initiating therapy.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that CYP2D6 PM should initiate metoprolol therapy at the lowest recommended starting dose, and titration should be performed with care and close monitoring for bradycardia. (Table 2) Standard dosing and care are recommended for intermediate metabolizers (IM) and NM of CYP2D6, but no recommendation is made for ultrarapid metabolizers (UM) given the limited data on this phenotype and beta-blocker response. (4)

The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP) has also published metoprolol dosing recommendations based on CYP2D6 genotype. For individuals who have a CYP2D6 gene variation that reduces the conversion of metoprolol to inactive metabolites (namely, the IM and PM phenotype), DPWG states that the clinical consequences are limited mainly to the occurrence of asymptomatic bradycardia. For CYP2D6 PM or IM, if a gradual reduction in heart rate is desired, or in the event of symptomatic bradycardia, DPWG recommends increasing the dose of metoprolol in smaller steps, prescribing no more than 25% (PM) or 50% (IM) of the standard dose, or both. For CYP2D6 UM, DPWG indicates that clinical response is hardly decreased at a dose of 200 mg/day. However, if efficacy is insufficient at this maximum dose, the DPWG recommends increasing the dose based on effectiveness and side effects up to a maximum of 2.5 times the normal dose, or selecting an alternative. (Table 3) (5).

PMID:28520381 | Bookshelf:NBK425389

2016 Sep 22 [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

Aripiprazole (brand names Abilify or Aristada) is an atypical antipsychotic used to manage schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, and in the treatment of Tourette syndrome. (1)

The metabolism and elimination of aripiprazole is mainly mediated through 2 enzymes, CYP2D6 and CYP3A4. Approximately 8% of Caucasians, 3–8% of Black/African Americans and up to 2% of Asians cannot metabolize CYP2D6 substrates and are classified as “poor metabolizers.” (2)

The FDA-approved drug label for aripiprazole states that in CYP2D6 poor metabolizers, half of the usual dose should be administered. In CYP2D6 poor metabolizers who are taking concomitant strong CYP3A4 inhibitors (for example, itraconazole, clarithromycin), a quarter of the usual dose should be used (Table 1) (1). The dosage reduction is the same regardless of the administration route (oral or long-acting injectable). (3)

The Dutch Pharmacogenetics Working group (DPWG) also recommends a reduced dosage for CYP2D6 poor metabolizers, “no more than 10 mg/day or 300 mg/month” (Table 2). No action is recommended for intermediate or ultrarapid metabolizers. While both of these metabolic variations alter the plasma concentrations of aripiprazole, there is no evidence that this increases the risk of reduced effectiveness or risk of side effects. (4)

In contrast to the recommendations by the FDA and DPWG, some recent studies have suggested CYP2D6 intermediate metabolizers may also require a dose decrease, but this was only based on aripiprazole clearance. (5, 6, 7, 8)

PMID:28520375 | Bookshelf:NBK385288

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