Complémentarité des méthodes numériques et symboliques en pharmacovigilance

National audienceLa pharmacovigilance a pour objet la surveillance du risque d'effet indésirable résultant de l'utilisation des médicaments et produits à usage humain. Elle consiste à détecter des « signaux » correspondant à des corrélations suspectes entre la prise d'un médicament et l'observation d'un effet indésirable. Les professionnels de santé sont tenus de signaler tout effet indésirable inattendu en envoyant un rapport a leur centre régional de pharmacovigilance, alimentant ainsi une base nationale. Pour faire face à la quantité de rapports stockés, des méthodes numériques fondées sur des mesures de disproportionnalité été proposées ; elles extraient efficacement les couples (médicament, effet indésirable) sur-représentés dans la base, en vue de leur evaluation par un expert. Toutefois, ces approches fournissent peu d'information aux experts pour leur permettre de comprendre pour quelles raisons ces signaux ont eté retenus. De plus, aucune information ne leur est transmise concernant la spécificité eventuelle d'un signal qui concernerait plus particulièrement une sous-population (sexe, âge). L'utilisation d'une approche symbolique comme l'Analyse de Concepts Formels (ACF), en complément des méthodes numériques existantes, nous a permis d'obtenir une meilleure « tracabilité » des signaux extraits en fournissant aux experts une vue synthétique du contenu de la base. De plus, l'utilisation d'une approche fondée sur les treillis permet de réduire l'espace de recherche, de détecter des associations complexes impliquant plusieurs médicaments et effets indésirables et d'identifier les spécificités liées aux diverses sous-populations. Nous illustrons ces atouts par une expérimentation sur la base régionale HEGP

A Knowledge Management Platform for Documentation of Case Reports in Pharmacovigilance

Most countries have developed information systems to report drug adverse effects. However, as in other domains where systematic reviews are needed, there is little guidance on how systematic documentation of drug adverse effects should be performed. The objective of the VigiTermes project is to develop a platform to improve documentation of pharmacovigilance case reports for the pharmaceutical industry and regulatory authorities. In order to improve systematic reviews of adverse drug reactions, we developed a prototype that first reproduces and standardizes search strategies, then extracts information from the Medline abstracts which were retrieved and annotates them. The platform aims at providing transparent access and analysis tools to pharmacovigilance experts investigating relevance of safety signals related to drugs. The platform's architecture consists in the integration of two vendor tools ITM® and Luxid® and one academic web service for knowledge extraction from medical literature. Whereas a manual search performed by a pharmacovigilance expert retrieved 578 publications, the system proposed a list of 229 publications thus decreasing time required for review by 60%. Recall was 70% and additional developments are required in order to improve exhaustivity

Vestibular disorders following BNT162b2 mRNA COVID-19 vaccination: A retrospective case series

International audienceBackground: There are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination. Purpose: We describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect. Methods: A retrospective analysis of cases of VD following BNT162b2 vaccination reported to the pharmacovigilance centre of Georges-Pompidou European Hospital (France), in 2021 was performed. In order to identify these cases from the pharmacovigilance database containing all our registered cases, we used the Standardised MedDRA Query (SMQ) ‘vestibular disorders’. Then we analysed cases with vestibular symptoms, based on the association of typical manifestations. The reporting rate was calculated based on the number of VD cases and the number of vaccinated patients. Results: Among 6608 cases reported to our centre related to COVID-19 vaccines during 2021, 34 VDs associated with BNT162b2 administration were included. They were mainly reported in females (79%), 62% occurred after the first dose and 32% were serious. Symptoms had completely resolved in 13 cases (38%). Vertigo was the most common symptom followed by balance disorders. Three patients received second dose without reappearance of VD. The final diagnosis was reported in 10 patients (six cases of vestibular neuritis, two cases of central VD, two cases of benign paroxysmal positional vertigo). The regional reporting rate was 26 [95% CI: 17–34] cases of VD per 1 million persons vaccinated. Conclusion: Although the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect

VigiTermes : une plateforme de recherche et d'analyse des publications scientifiques au service de la pharmacovigilance

National audienceLa réglementation impose une identification systématique des effets indésirables des médicaments. La plupart des pays se sont dotés de systèmes d'information d'aide à la documentation de ces effets. La tâche est rendue difficile par la multiplicité des sources et le peu d'outils fédérateurs existant pour accéder, rechercher et analyser l'information autour des médicaments. L'objectif du projet VigiTermes est de développer une plateforme pour améliorer la documentation des rapports de cas de pharmacovigilance et de proposer des outils d'accès et d'analyse pour les experts pharmacovigilants, dont l'objectif est d'enquêter sur la détection de nouveaux cas (signaux). Dans ce cadre, nous avons développé un prototype qui reproduit et standardise les stratégies de recherche documentaire formulées par les pharmacovigilants, récupère les résumés PubMed pertinents et en extrait de l'information autour des médicaments et de leurs effets secondaires potentiels

Detection of Drug–Drug Interactions Inducing Acute Kidney Injury by Electronic Health Records Mining

International audienceBackground and Objective : While risk of acute kidney injury (AKI) is a well documented adverse effect of some drugs, few studies have assessed the relationship between drug–drug interactions (DDIs) and AKI. Our objective was to develop an algorithm capable of detecting potential signals on this relationship by retrospectively mining data from electronic health records.Material and methods : Data were extracted from the clinical data warehouse (CDW) of the Hôpital Européen Georges Pompidou (HEGP). AKI was defined as the first level of the RIFLE criteria, that is, an increase ≥50 % of creatinine basis. Algorithm accuracy was tested on 20 single drugs, 10 nephrotoxic and 10 non-nephrotoxic. We then tested 45 pairs of non-nephrotoxic drugs, among the most prescribed at our hospital and representing distinct pharmacological classes for DDIs.Results : Sensitivity and specificity were 50 % [95 % confidence interval (CI) 23.66–76.34] and 90 % (95 % CI 59.58–98.21), respectively, for single drugs. Our algorithm confirmed a previously identified signal concerning clarithromycin and calcium-channel blockers (unadjusted odds ratio (ORu) 2.92; 95 % CI 1.11–7.69, p = 0.04). Among the 45 drug pairs investigated, we identified a signal concerning 55 patients in association with bromazepam and hydroxyzine (ORu 1.66; 95 % CI 1.23–2.23). This signal was not confirmed after a chart review. Even so, AKI and co-prescription were confirmed for 96 % (95 % CI 88–99) and 88 % (95 % CI 76–94) of these patients, respectively.Conclusion : Data mining techniques on CDW can foster the detection of adverse drug reactions when drugs are used alone or in combination

Pharmacology and social media: Potentials and biases of web forums for drug mention analysis-case study of France

International audienceThe aim of this study is to analyze drug mentions in web forums to evaluate the utility of this data source for drug post-marketing studies. We automatically annotated over 60 million posts extracted from 21 French web forums. Drug mentions detected in this corpus were matched to drug names in a French drug database (Theriaque®). Our analysis showed that a high proportion of the most frequent drug mentions in the selected web forums correspond to drugs that are usually prescribed to young women, such as combined oral contraceptives. The most mentioned drugs in our corpus correlated weakly to the most prescribed drugs in France but seemed to be influenced by events widely reported in traditional media. In this article, we conclude that web forums have high potential for post-marketing drug-related studies, such as pharmacovigilance, and observation of drug utilization. However, the bias related to forum selection and the corresponding population representativeness should always be taken into account

Intramuscular Vaccination in Adults with Therapeutic Anticoagulation in the Era of COVID-19 Vaccines Outbreak: A Practical Review

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Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 534 liters, 1,530 liters, 144 liters/h and 90.9 liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg · h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated