Dataset Information

Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study.

ABSTRACT: This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients.

SUBMITTER: Rollason V

PROVIDER: S-EPMC7711785 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study.

Rollason Victoria V Lloret-Linares Célia C Lorenzini Kuntheavy Ing KI Daali Youssef Y Gex-Fabry Marianne M Piguet Valérie V Besson Marie M Samer Caroline C Desmeules Jules J

Journal of personalized medicine 20201027 4

This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. ...[more]

PMID: 33121061

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Project description:RationaleCytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive.ObjectivesWe explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline.MethodsPatients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation.ResultsP450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea.ConclusionsIn this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.

Project description:BackgroundCo-trimoxazole has been reported as a common culprit drug for various cutaneous adverse drug reactions (CADRs). However, information on genotypic and phenotypic characteristics is still limited. We aimed to study clinical characteristics, genetic suitability, laboratory findings, and treatment outcomes in patients with co-trimoxazole-induced CADR and determine variables associated with severe cutaneous adverse reactions (SCARs).MethodsThe medical records of all patients diagnosed with co-trimoxazole-induced CADR during October 2015 and October 2021 were reviewed. Clinical characteristics and laboratory investigation with an emphasis on human leukocyte antigen (HLA) class I and HLA-DRB1 results linked to subtypes of cutaneous adverse reactions were evaluated.ResultsSeventy-two patients diagnosed with co-trimoxazole-induced CADR were included in the study. Mean age at diagnosis was 38.0 ± 14.6 years old, and 72% were female. Subtypes of reactions included maculopapular eruption (MPE; 56.9%), drug reaction with eosinophilia and systemic symptoms (DRESS; 23.6%), Stevens-Johnson syndrome (SJS; 12.5%), fixed drug eruption (4.2%), and urticaria (2.8%). Characteristics that were significantly associated with SCARs included male gender (OR = 3.01, 95% CI: 1.04-8.75), HIV infection (OR = 3.48, 95% CI: 1.13-10.75), prophylactic use of co-trimoxazole (OR = 4.89, 95% CI: 1.54-15.57), and co-trimoxazole administration longer than 10 days (OR = 7.65, 95% CI: 2.57-22.78). HLA-B*38:02 was associated with co-trimoxazole-induced SJS, while HLA-A*11:01, HLA-B*13:01, and HLA-DRB1*12:01 were associated with co-trimoxazole-induced DRESS. HLA-B*52:01 was associated with co-trimoxazole-induced MPE.ConclusionsCo-trimoxazole could induce various phenotypes of CADRs. Genotypic and phenotypic factors that may potentially predict co-trimoxazole-induced SCARs include male gender, HIV infection, prophylactic and prolonged drug use, as well as the presence of HLA-A*11:01, HLA-B*13:01, HLA-B*38:02, or HLA-DRB1*12:01 alleles.

Dataset Information

Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study.

Publications

Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study.

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