Policymaking for Orphan Drugs and Its Challenges.

AMA J Ethics. 2015 Aug;17(8):776-9

Authors: Rhee TG

PMID: 26270879 [PubMed - indexed for MEDLINE]

Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain.

Brain. 2015 Dec;138(Pt 12):e400

Authors: Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, García-Redondo A, Povedano M, Lladó A, Álvarez V, Sánchez-Juan P, Pardo J, Jericó I, Vázquez-Costa J, Sevilla T, Cardona F, Indakoechea B, Moreno F, Fernández-Torrón R, Muñoz-Llahuna L, Moreno-Grau S, Rosende-Roca M, Vela Á, Muñoz-Blanco JL, Combarros O, Coto E, Alcolea D, Fortea J, Lleó A, Sánchez-Valle R, Esteban-Pérez J, Ruiz A, Pastor P, López De Munain A, Pérez-Tur J, Clarimón J, Dementia Genetics Spanish Consortium (DEGESCO)

PMID: 26152333 [PubMed - indexed for MEDLINE]

Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

PLoS One. 2015;10(6):e0128113

Authors: Andersson C, Kvist PH, McElhinney K, Baylis R, Gram LK, Pelzer H, Lauritzen B, Holm TL, Hogan S, Wu D, Turpin B, Miller W, Palumbo JS

Abstract
The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

PMID: 26098308 [PubMed - indexed for MEDLINE]

Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.

PLoS One. 2015;10(6):e0128074

Authors: Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, PRO-KIIDS Research Group, Kugathasan S

Abstract
BACKGROUND: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
METHODS: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
CONCLUSIONS: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

PMID: 26098103 [PubMed - indexed for MEDLINE]

The Telehealth Enhancement of Adherence to Medication (TEAM) in pediatric IBD trial: Design and methodology.

Contemp Clin Trials. 2015 Jul;43:105-13

Authors: Hommel KA, Gray WN, Hente E, Loreaux K, Ittenbach RF, Maddux M, Baldassano R, Sylvester F, Crandall W, Doarn C, Heyman MB, Keljo D, Denson LA

Abstract
Medication nonadherence is a significant health care issue requiring regular behavioral treatment. Lack of sufficient health care resources and patient/family time commitment for weekly treatment are primary barriers to receiving appropriate self-management support. We describe the methodology of the Telehealth Enhancement of Adherence to Medication (TEAM) trial for medication nonadherence in pediatric inflammatory bowel disease (IBD). For this trial, participants 11-18 years of age will be recruited from seven pediatric hospitals and will complete an initial 4-week run in to assess adherence to a daily medication. Those who take less than 90% of their prescribed medication will be randomized. A total of 194 patients with IBD will be randomized to either a telehealth behavioral treatment (TBT) arm or education only (EO) arm. All treatments will be delivered via telehealth video conferencing. The patients will be assessed at baseline, post-treatment, 3, 6, and 12 months. We anticipate that participants in the TBT arm will demonstrate a statistically significant improvement at post-treatment and 3-, 6-, and 12-month follow-up compared to participants in the EO arm for both medication adherence and secondary outcomes (i.e., disease severity, patient quality of life, and health care utilization). If efficacious, the TEAM intervention could be disseminated broadly and reduce health care access barriers so that the patients could receive much needed self-management intervention.

PMID: 26003436 [PubMed - indexed for MEDLINE]

Pharmacological, Pharmacokinetic, and Pharmacogenomic Aspects of Functional Gastrointestinal Disorders.

Gastroenterology. 2016 Feb 18;

Authors: Camilleri M, Bueno L, Andresen V, De Ponti F, Choi MG, Lembo A

Abstract
This article reviews medications commonly used for the treatment of patients with functional gastrointestinal disorders. Specifically, we review the animal models that have been validated for the study of drug effects on sensation and motility; the preclinical pharmacology, pharmacokinetics, and toxicology usually required for introduction of new drugs; the biomarkers that are validated for studies of sensation and motility endpoints with experimental medications in humans; the pharmacogenomics applied to these medications and their relevance to the FGIDs; and the pharmacology of agents that are applied or have potential for the treatment of FGIDs, including psychopharmacologic drugs.

PMID: 27144621 [PubMed - as supplied by publisher]

Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV.

Gastroenterology. 2016 Feb 19;

Authors: Drossman DA

Abstract
Functional gastrointestinal disorders (FGIDs), the most common diagnoses in gastroenterology are recognized by morphological and physiological abnormalities that often occur in combination including motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota and altered central nervous system processing. Research on these gut-brain interaction disorders is based on using specific diagnostic criteria. The Rome Foundation has played a pivotal role in creating diagnostic criteria thus operationalizing the dissemination of new knowledge in the field of FGIDs. Rome IV is a compendium of the knowledge accumulated since Rome III was published 10 years ago. It improves upon Rome III by: 1) updating the basic and clinical literature, 2) offering new information on gut microenvironment, gut-brain interactions, pharmacogenomics, biopsychosocial, gender and cross cultural understandings of FGIDs, 3) reduces the use of imprecise and occassionally stigmatizing terms when possible, 4) uses updated diagnostic algorithms, 5) incorporates information on the patient illness experience, and physiological subgroups or biomarkers that might lead to more targeted treatment. This introductory article sets the stage for the remaining 17 articles that follow and offers an historical overview of the FGIDs field, differentiates FGIDs from motility and structural disorders, discusses the changes from Rome III, reviews the Rome committee process, provides a biopsychosocial pathophysiological conceptualization of FGIDs, and offers an approach to patient care.

PMID: 27144617 [PubMed - as supplied by publisher]

Ligand cluster-based protein network and ePlatton, a multi-target ligand finder.

J Cheminform. 2016;8:23

Authors: Du Y, Shi T

Abstract
BACKGROUND: Small molecules are information carriers that make cells aware of external changes and couple internal metabolic and signalling pathway systems with each other. In some specific physiological status, natural or artificial molecules are used to interact with selective biological targets to activate or inhibit their functions to achieve expected biological and physiological output. Millions of years of evolution have optimized biological processes and pathways and now the endocrine and immune system cannot work properly without some key small molecules. In the past thousands of years, the human race has managed to find many medicines against diseases by trail-and-error experience. In the recent decades, with the deepening understanding of life and the progress of molecular biology, researchers spare no effort to design molecules targeting one or two key enzymes and receptors related to corresponding diseases. But recent studies in pharmacogenomics have shown that polypharmacology may be necessary for the effects of drugs, which challenge the paradigm, 'one drug, one target, one disease'. Nowadays, cheminformatics and structural biology can help us reasonably take advantage of the polypharmacology to design next-generation promiscuous drugs and drug combination therapies.
RESULTS: 234,591 protein-ligand interactions were extracted from ChEMBL. By the 2D structure similarity, 13,769 ligand emerged from 156,151 distinct ligands which were recognized by 1477 proteins. Ligand cluster- and sequence-based protein networks (LCBN, SBN) were constructed, compared and analysed. For assisting compound designing, exploring polypharmacology and finding possible drug combination, we integrated the pathway, disease, drug adverse reaction and the relationship of targets and ligand clusters into the web platform, ePlatton, which is available at http://www.megabionet.org/eplatton.
CONCLUSIONS: Although there were some disagreements between the LCBN and SBN, communities in both networks were largely the same with normalized mutual information at 0.9. The study of target and ligand cluster promiscuity underlying the LCBN showed that light ligand clusters were more promiscuous than the heavy one and that highly connected nodes tended to be protein kinases and involved in phosphorylation. ePlatton considerably reduced the redundancy of the ligand set of targets and made it easy to deduce the possible relationship between compounds and targets, pathways and side effects. ePlatton behaved reliably in validation experiments and also fast in virtual screening and information retrieval.Graphical abstractCluster exemplars and ePlatton's mechanism.

PMID: 27143991 [PubMed]

Potential utility of precision medicine for older adults with polypharmacy: a case series study.

Pharmgenomics Pers Med. 2016;9:31-45

Authors: Finkelstein J, Friedman C, Hripcsak G, Cabrera M

Abstract
Pharmacogenomic (PGx) testing has been increasingly used to optimize drug regimens; however, its potential in older adults with polypharmacy has not been systematically studied. In this hypothesis-generating study, we employed a case series design to explore potential utility of PGx testing in older adults with polypharmacy and to highlight barriers in implementing this methodology in routine clinical practice. Three patients with concurrent chronic heart and lung disease aged 74, 78, and 83 years and whose medication regimen comprised 26, 17, and 18 drugs, correspondingly, served as cases for this study. PGx testing identified major genetic polymorphisms in the first two cases. The first case was identified as "CYP3A4/CYP3A5 poor metabolizer", which affected metabolism of eleven prescribed drugs. The second case had "CYP2D6 rapid metabolizer" status affecting three prescribed medications, two of which were key drugs for managing this patient's chronic conditions. Both these patients also had VKORC1 allele *A, resulting in higher sensitivity to warfarin. All cases demonstrated a significant number of potential drug-drug interactions. Both patients with significant drug-gene interactions had a history of frequent hospitalizations (six and 23, respectively), whereas the person without impaired cytochrome P450 enzyme activity had only two acute episodes in the last 5 years, although he was older and had multiple comorbidities. Since all patients received guideline-concordant therapy from the same providers and were adherent to their drug regimen, we hypothesized that genetic polymorphism may represent an additional risk factor for higher hospitalization rates in older adults with polypharmacy. However, evidence to support or reject this hypothesis is yet to be established. Studies evaluating clinical impact of PGx testing in older adults with polypharmacy are warranted. For practical implementation of pharmacogenomics in routine clinical care, besides providing convincing evidence of its clinical effectiveness, multiple barriers must be addressed. Introduction of intelligent clinical decision support in electronic medical record systems is required to address complexities of simultaneous drug-gene and drug-drug interactions in older adults with polypharmacy. Physician training, clear clinical pathways, evidence-based guidelines, and patient education materials are necessary for unlocking full potential of pharmacogenomics into routine clinical care of older adults.

PMID: 27143951 [PubMed]

History repeats itself: the family medication history and pharmacogenomics.

Pharmacogenomics. 2016 May 4;

Authors: Smith TR, Kearney E, Hulick PJ, Kisor DF

Abstract
Related to many drug gene-product interactions, application of pharmacogenomics can lead to improved medication efficacy while decreasing or avoiding adverse drug reactions. However, utilizing pharmacogenomics without other information does not allow for optimal medication therapy. Currently, there is a lack of documentation of family medication history, in other words, inefficacy and adverse reactions across family members throughout generations. The family medication history can serve as an impetus for pharmacogenomic testing to explain lack of medication efficacy or an adverse drug reaction and pre-emptive testing can drive recognition and documentation of medication response in family members. We propose combining the family medication history via pedigree construction with pharmacogenomics to further optimize medication therapy. We encourage clinicians to combine family medication history with pharmacogenomics.

PMID: 27143300 [PubMed - as supplied by publisher]

[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