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 Mar 23 [updated 2025 Jun 23]. 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

Amitriptyline is a tricyclic antidepressant used in the treatment of several psychiatric disorders, including major depression, obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, and bulimia. Amitriptyline also has different off-label uses, including migraine prevention, neuropathic pain management, fibromyalgia, and enuresis (bedwetting) (1).

Tricyclic antidepressants (TCAs) primarily mediate their therapeutic effect by inhibiting the reuptake of both serotonin and norepinephrine, leaving more neurotransmitter in the synaptic cleft stimulating the neuron. Given that the tricyclics can also block different receptors (H1 histamine, α1-adrenergic, and muscarinic receptors), side effects are common. As such, selective serotonin reuptake inhibitors (SSRIs) have largely replaced the use of TCAs; however, TCAs still have an important use in specific types of depression and other conditions.

Amitriptyline is metabolized mainly via CYP2C19 and CYP2D6 pathways. Metabolism by CYP2C19 results in active metabolites, including nortriptyline, which is also a tricyclic antidepressant. Metabolism catalyzed by CYP2D6 results in the formation of the less active 10-hydroxy metabolite. Both the CYP2D6 and CYP2C19 genes are highly polymorphic, resulting in proteins with different enzyme activity or expression levels. Individuals who are CYP2D6 “ultrarapid metabolizers” (UM) have more than 2 normal function alleles (multiple copies), whereas 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.

The FDA-approved drug label for amitriptyline states that CYP2D6 PM have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. The FDA recommendations also include monitoring tricyclic antidepressant plasma levels whenever a tricyclic antidepressant is co-administered with another drug known to be an inhibitor of CYP2D6 (Table 1) (1).

The Dutch Pharmacogenetic Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have issued recommendations for altered dosing based on CYP2D6 metabolizer phenotype (Table 2) (2, 3). Individuals who are CYP2D6 UM may require up to 1.6 times the normal dose, though cardiac toxicity risk may indicate use of an antidepressant that is less dependent upon CYP2D6 metabolism, such as citalopram or sertraline. Dose reductions are recommended for CYP2D6 intermediate metabolizer (IM) individuals (75% of normal dose) and CYP2D6 PM individuals (60% of normal dose), along with monitoring for side effects and plasma drug levels. (3). The DPWG does not recommend any changes in dosing based on CYP2C19 metabolizer status, since the combined dose of amitriptyline and the active metabolite nortriptyline are not significantly impacted. (2)

In 2016, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published dosing recommendations for tricyclic antidepressants based on CYP2C19 and CYP2D6 metabolizer status, either individually or in combination (Table 3, Table 4) (4). For CYP2D6 UM, CPIC recommends avoiding the use of a tricyclic due to the potential lack of efficacy, and to consider an alternative drug not metabolized by CYP2D6. If a TCA is still warranted, CPIC recommends considering titrating the TCA to a higher target dose (compared with CYP2D6 normal metabolizers, “NM”) and using therapeutic drug monitoring to guide dose adjustments. For CYP2D6 IM, CPIC recommends considering a 25% reduction of the starting dose, and for CYP2D6 PM, to avoid the use of tricyclics because of the potential for side effects. If a tricyclic is still warranted for CYP2D6 PM, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects.

For CYP2C19 UM, CPIC recommends avoiding the use of tertiary amines (for example, amitriptyline) due to the potential for a sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19, such as the secondary amines nortriptyline or desipramine. For CYP2C19 PMs, CPIC recommends avoiding tertiary amine use due to the potential for sub-optimal response, and to consider an alternative drug not metabolized by CYP2C19. If a tertiary amine is still warranted for CYP2C19 PMs, CPIC recommends considering a 50% reduction of the starting dose while monitoring drug plasma concentrations to avoid side effects (4). 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 (4).

PMID:28520380 | Bookshelf:NBK425165

2015 Oct 14 [updated 2025 Jun 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

Carbamazepine (brand names include Carbatrol, Epitol, Equetro, and Tegretol) is an effective antiseizure drug that is often used as a first-line agent in the treatment of epilepsy. Carbamazepine is also used to treat bipolar disorder and to relieve pain in trigeminal neuralgia.

Hypersensitivity reactions associated with carbamazepine can occur in up to 10% of patients, and typically affect the skin. Some of these reactions are mild, as in the case of maculopapular exanthema (MPE); however, conditions such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening.

The risk of hypersensitivity is increased by the presence of specific human leukocyte antigen (HLA) alleles. The HLA-B*15:02 allele is strongly associated with carbamazepine-induced SJS/TEN in populations where this allele is most common, such as in Southeast Asia.

According to the FDA-approved drug label for carbamazepine, testing for HLA-B*15:02 should be done for all patients with ancestry in populations with increased frequency of HLA-B*15:02, prior to initiating carbamazepine therapy (Table 1). The label states that greater than 15% of the population is reported HLA-B*15:02 positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. The label states that South Asians, including Indians, appear to have intermediate prevalence of HLA-B*15:02, averaging 2 to 4%, but higher in some groups. In Japan and Korea, the HLA- B*15:02 is present in less than 1% of the population. In individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans), the HLA-B*15:02 allele is largely absent. These prevalence rates of HLA-B*15:02 may be used to guide which patients should be screened. However, the FDA cautions to keep in mind the limitations of prevalence rate data when deciding which patients to screen. This is because of the wide variability in HLA-B*15:02 rates (even within ethnic groups), the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry (1).

The FDA label also states that carbamazepine should not be used in patients who are positive for HLA-B*15:02 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN.

The HLA-A*31:01 allele may also be a risk factor for SJS/TEN but is more strongly associated with other carbamazepine-induced reactions, such as DRESS and MPE. HLA-A*31:01 is found in most populations, worldwide. HLA-B*15:11 is another allele that has been linked with SJS/TEN. The FDA states that the risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*31:01, but does not discuss HLA-B*15:11 (1).

Carbamazepine dosing guidelines based on HLA genotype have been published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) (2, 3, 4, 5).

DPWG recommendations include avoiding the use of carbamazepine and selecting an alternative, if possible, for individuals positive for HLA-B*15:02, HLA-A*31:01 and HLA-B*15:11 (Table 2). CPIC recommendations include not using carbamazepine in carbamazepine-naïve patients who are positive for HLA-B*15:02 and any HLA-A*31:01 genotype (or HLA-A*31:01 genotype unknown) (Table 3). CPNDS recommends genetic testing for all carbamazepine-naïve patients before they start treatment, with a moderate level of evidence for HLA-A*31:01 testing, and strong to optional evidence for HLA-B*15:02 testing (based on the frequency of HLA-B*15:02 in the population the patient originates from, and if this is known or not) (Table 4).

PMID:28520367 | Bookshelf:NBK321445

2017 Jan 25 [updated 2025 May 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

Sofosbuvir is an antiviral agent used in the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is FDA-approved to treat individuals infected with HCV genotypes 1, 2, 3, and 4, as part of a combination antiviral treatment regimen (1). The most prevalent genotype worldwide is HCV genotype 1, and HCV genotype 3 is the second most prevalent (2). Sofosbuvir may also be used as part of the treatment regimen of HCV genotypes 5 or 6 (3).

Approximately 180 million people worldwide are infected with chronic hepatitis C, which is a major cause of chronic liver disease, cirrhosis, and liver cancer. Viral eradication is suboptimal with peginterferon plus ribavirin-based therapy, with just under half of individuals with HCV genotype 1 infection achieving a sustained virological response (SVR) after 24 weeks (4). An SVR is defined as undetectable HCV RNA by the end of treatment or at a specific number of weeks after the initiation of treatment; for example, undetectable HCV RNA at 12 weeks is annotated as SVR12.

Direct-acting antivirals (DAAs), such as sofosbuvir, were developed to improve viral eradication rates. They target HCV-encoded proteins involved in viral replication and infection. Sofosbuvir, a key component of DAA regimens, targets NS5B polymerase, the viral enzyme required for HCV RNA replication.

Sofosbuvir may be used with peginterferon. The genetic variant rs12979860, located in the INFL4 gene, is a strong predictor of response to peginterferon-based therapies. The variant is a C to T change—individuals with the favorable “C/C” genotype have approximately a 2-fold higher likelihood of achieving SVR compared with individuals with CT or TT genotype (5). (Note, because the association of rs12979860 with treatment response was reported several years before the discovery of IFNL4, the variant is commonly referred to as IL28B, which was the previous name for the IFNL3 gene.)

For specific treatment regimens that include sofosbuvir, although the IFNL4 variant still influences treatment outcomes, the SVR remains relatively high for all IFNL4 genotypes. For example, in the NEUTRINO study, the SVR12 rate was 99% in individuals with baseline C/C alleles and 87% in individuals with non-C/C alleles. The individuals in this study had HCV genotype 1 or 4 infection and were receiving sofosbuvir plus peginterferon plus ribavirin therapy (1, 6).

The drug label for sofosbuvir also discusses viral resistance. In cell culture, the amino acid substitution S282T in the viral NS5B polymerase is associated with reduced susceptibility to sofosbuvir (1). During the ELECTRON trial, this substitution was transiently detected in one individual who relapsed during sofosbuvir monotherapy. However, the clinical significance of such substitutions remains unknown (1).

PMID:28520377 | Bookshelf:NBK409960

2025 Apr 15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.

ABSTRACT

Pirfenidone is an orally available pyridinone derivative that inhibits collagen formation and is used to treat idiopathic pulmonary fibrosis. Elevations in serum enzyme levels during pirfenidone therapy are not uncommon, but it has yet to be implicated in cases of clinically apparent liver injury with jaundice.

PMID:31644078 | Bookshelf:NBK548769