Pharmacogenetics of hypersensitivity drug reactions

Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions

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

Interactions médicamenteuses et hypolipémiants

Les rhabdomyolyses attribuables aux statines et aux fibrates surviennent fréquemment lorsque les concentrations plasmatiques de ces médicaments sont très élevées, notamment au cours d'interactions médicamenteuses. Les statines présentent une faible biodisponibilité du fait d'un premier passage hépatique important exposant ces molécules à des élévations parfois très importantes de leurs concentrations plasmatiques lorsqu'un médicament inhibe ce phénomène de premier passage. La simvastatine et l'atorvastatine métabolisées par le cytochrome P450 3A4 (CYP3A4) sont les molécules pour lesquelles le risque d'interactions médicamenteuses avec les inhibiteurs du CYP3A4 est le plus élevé. La fluvastatine métabolisée par le CYP2C9 présente un potentiel d'interactions médicamenteuses bien inférieur. Le premier passage de la pravastatine ne fait pas intervenir de CYP, son potentiel d'interactions médicamenteuses est le plus faible. La biodisponibilité proche de 100 % des fibrates minimise leur risque d'interactions médicamenteuses. Cependant ils occasionnent parfois des modifications de la pharmacocinétique d'autres médicaments qui peuvent leur être associés. Seuls la simvastatine, la pravastatine et le gemfibrozil ont démontré au cours d'essais contrôlés à long terme leur efficacité dans la prévention des complications de l'athérosclérose. La simvastatine présente le plus fort potentiel d'interactions médicamenteuses, la pravastatine et le gemfibrozil les plus faibles

Pharmacogénétique de l'acide mycophénolique en transplantation rénale

PARIS-BIUP (751062107) / SudocSudocFranceF

Pharmacogénétique en transplantation rénale

1) Étude du polymorphisme génétique de la vitamine K époxyde réductase (VKORC1) et le risque de surdosage en anti-vitamine K (AVK). Précédemment, nous avons réalisé une étude prospective de type cas-témoin dans le but de d identifier des facteurs de risque de surdosage en AVK. La même population a été ré-analysée, en ajoutant un nouveau facteur génétique (VKORC1 1173C>T). Nous avons montré dans cette étude que le risque de surdosage est significativement plus important chez les patients 1173TT et les patients 1173CT comparativement aux patients 1173CC avec un risque relatif de 10,5 et 2,3 respectivement. 2) Étude des facteurs génétiques de survenue de rejet aigu et des facteurs prédictifs de la fonction à long terme du greffon en transplantation rénale. A partir d une cohorte de 288 patients transplantés, nous avons montré, dans un premier temps, que la fonction à long terme des greffons était supérieure chez les patients porteurs de l haplotype VKORC1*2/*2 que chez les non porteurs (HR: 0.34, 95% CI: 0.26 - 0.87, P=0.02). Dans un second temps, nous avons pu identifier une association entre le polymorphisme génétique de CYP3A5 et la posologie quotidienne du tacrolimus et la survenue de rejet aigu au cours de la première année de greffe. Dans une population de 136 patients transplantés rénaux, nous avons montré que les sujets porteurs d au moins un allèle CYP3A5*1 avaient besoin une posologie plus importante du tacrolimus pour atteindre une concentration à l état d équilibre. A 1 mois post-greffe, l incidence de rejet aigu était plus importante chez les sujets porteurs de deux allèles CYP3A5*1 que les non porteurs (38% et 10% respectivement).PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / 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

Impact of Pregnancy on Psychotropic Medication Prescription: a French Cohort Study

Objectives. To determine if and when prescription of psychotropic medication in women is modified by pregnancy. Method. Psychotropic prescription of 87 213 pregnant women affiliated with the French General Health System was examined. Period of analyses lasted 17 months to cover 4 months before and after pregnancy. A comparable cohort of 87 213 non pregnant women constituted the control group. Results. More than half of pregnant women to whom a psychoactive drug was prescribed were novel users during all three trimesters and after delivery. Prevalence of psychotropic medication before pregnancy is comparable to that of non-pregnant women. Rate of psychotropic medication during the peripartum stayed high, even though it decreased by half during the first trimester, showing a “pregnancy impact effect”. Conclusions. Data show a dramatic impact of pregnancy. More information on specific patterns of prescription needs to be gained in order to establish decision-making models for psychotropic prescription during pregnancy

Personalized Medicine: how to Switch from the Concept to the Integration into the Clinical Development Plan to Obtain Marketing Authorization

One of the challenges of the coming years is to personalize medicine in order to provide each patient with an individualized treatment plan. The three objectives of personalized medicine are to refine diagnosis, rationalize treatment and engage patients in a preventive approach. Personalization can be characterized by various descriptors whether related to the field, biology, imaging, type of lesion of the entity to be treated, comorbidity factors, coprescriptions or the environment As part of personalized medicine focused on biological markers including genetics or genomics, the integration of the clinical development plan to obtain marketing authorization may be segmented in 3 stages with a known descriptor identified before clinical development, a known descriptor discovered during clinical development or a known descriptor known after clinical development. For each stage, it is important to clearly define the technical optimization elements, to specify the expectations and objectives, to examine the methodological aspects of each clinical development phase and finally to consider the fast changing regulatory requirements in view of the few registered therapeutics complying with the definition of personalized medicine as well as the significant technological breakthroughs according to the screened and selected biomarkers. These considerations should be integrated in view of the time required for clinical development from early phase to MA, i.e. more than 10 years. Moreover, business models related to the economic environment should be taken into account when deciding whether or not to retain a biomarker allowing the selection of target populations in a general population