Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters.

OBJECTIVES: Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multi-drug-resistance 1 (MDR1) gene coding for P-glycoprotein. METHODS: Thirty-two healthy volunteers were recruited in three pharmacokinetic drug interaction studies. The data after a single oral administration of digoxin alone were pooled. All subjects were genotyped for the MDR1 C3435T and G2677T/A genotypes. The concentration-time profile of digoxin was established using 12-16 blood samples taken between 15 min and 72 h after administration. We modelled the pharmacokinetics of digoxin using non-linear mixed-effect models. Parameter estimation was performed using the stochastic approximation EM method (SAEM). We used three methods to select the covariate model: selection from a full model using Wald tests, forward inclusion using the log-likelihood ratio test and model selection using the Bayesian Information Criterion. RESULTS: The three covariate inclusion methods led to the same final model. Carriers of two T alleles for the C3435T polymorphism in exon 26 of MDR1 had a lower apparent volume of distribution than carriers of a C allele. The only other covariate effect was a shorter absorption time-lag in women. CONCLUSION: The apparent volume of distribution of digoxin is lower in TT subjects, probably reflecting differences in bioavailability. Non-linear mixed-effect models can be useful for detecting the influence of covariates on pharmacokinetic parameters

Special RepoRt Practical recommendations for pharmacogenomics- based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics

medical practice Oncology drugs A full day was dedicated to oncology covering germline as well as tumor pharmacogenomics. Three major examples were discussed. Response to tyrosine kinase inhibitors owing to activating EGFR mutations in non-small-cell lung cancer Miguel A Molina from Instituto Universitario USP Dexeus, Barcelona, presented the results of a national survey indicating the usefulness of tumor EGFR pharmacogenomics in order to define tumors that will respond (owing to activating mutations) to EGF receptor (EGFR) antagonists (tyrosine kinase inhibitors) [1]. Additional recent publications have confirmed the usefulness of EGFR pharmacogenomics in non-small-cell lung cancer (NSCLC) [2,3]. Tumor samples can be obtained from tumor biopsies, possibly followed by laser microdissection -or circulating blood tumor cells. Activating mutations are observed in 15% of The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6 -tamoxifen, TPMT-azathioprine -6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests. KEYWORDS: adverse drug reaction azathioprine cetuximab clopidogrel gefitinib genetic testing pharmacogenetics statins tacrolimus tamoxifen warfari

More rapid blood interferon α2 decline in fatal versus surviving COVID-19 patients

BackgroundThe clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection.ObjectiveTo study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19.MethodsOne hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome.ResultsAlthough the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14–8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19.ConclusionThese findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs.Clinical trial registrationhttps://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584

Dépression et réponse aux antidépresseurs (influence du polymorphisme génétique 5-HTTLPR du transporteur de la sérotonine)

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Rôle d'un polymorphisme génétique de la vitamine K époxyde réductase (VKOR) dans la plus grande sensibilité des asiatiques aux anticoagulants oraux

PARIS-BIUP (751062107) / SudocSudocFranceF

Rôle du polymorphisme génétique MDR1 dans le transport des médicaments et la variabilité interindividuelle de la réponse aux médicaments

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Pharmacoresistant Severe Mental Health Disorders in Children and Adolescents: Functional Abnormalities of Cytochrome P450 2D6

BackgroundSevere mental health disorders in children and adolescents represent a major public health problem. Despite adequate drug treatment, some patients develop pharmacoresistant disease. As a consequence, physicians are confronted with prescribing challenges, prolonged hospitalization and increased risk of adverse events, thus aggravating short-, medium-, and long-term prognosis. The majority of psychotropic treatments, particularly antipsychotics and antidepressants, are metabolized at hepatic level by cytochrome P450 (CYP), particularly by CYP3A4 and CYP2D6. Several CYP2D6 genetic polymorphisms are described to be associated with ultrarapid (UM) or poor drug metabolism (PM), inducing clinical resistance and/or adverse events, and might therefore be related to pharmacoresistant severe mental health disease.Case presentationA total of nine pharmacoresistant patients (four females, five males) aged 11–16 (mean 14.1) years have been genotyped for CYP2D6 between January, 2015 and April, 2016. Patients were diagnosed with schizophrenia (n = 5), autism spectrum disorders (n = 2), intellectual disability with challenging behavior (n = 2), oppositional defiant disorder (n = 1), and post-traumatic stress and borderline personality disorders (n = 1). They had a treatment history with on average 6.1 (3–9) psychotropic, 5 (3–7) antipsychotic, and 3.4 (2–5) CYP2D6-metabolized antipsychotic and antidepressant molecules. Five patients (56%) presented functional anomalies of the CYP2D6 gene: three patients were UM metabolizers with gene duplication and two patients were PM with *4/*41 and *3/*4 polymorphisms.ConclusionFunctional anomalies of CYP2D6 concerned more than half of our pediatric inpatient sample with pharmacoresistant disease. However, our case reports are limited by the low sample size. Nevertheless, knowledge of individual metabolism and in particular CYP2D6 genotyping should be considered for clinical workup and therapy adjustment in resistant patients in child and adolescent psychiatry and might permit better treatment outcome, increased treatment adherence and diminished adverse events