Various approaches to postmarketing drug safety monitoring

Before being launched on the market, a medicinal product must have been demonstrated of good quality, effective and safe. However, rare adverse drug reactions or those occurring after long-term use may not always be detected during the clinical development of a drug. Therefore, continuous drug safety monitoring, or pharmacovigilance, is essential during the whole lifecycle of a drug, including after the market authorization. This thesis provides an overview of different tools available for the postmarketing surveillance of drug safety. Classic pharmacovigilance is based on spontaneous reports of individual cases. Postmarketing studies are also useful to evaluate safety in certain populations (e.g. children, pregnant women, elderly) or to assess the impact of certain risk factors (e.g. pharmacogenetics). On the other hand, drug-drug interaction can lead to toxicity or to therapeutic failure when the systemic exposure of the victim drug is modified by a perpetrator drug. Finally, data and text mining strategies are useful when a large amount of data have to be explored, such as global pharmacovigilance databases, electronic health records, or social media

Aspects pharmacodynamiques et pharmacocinétiques d'une combinaison de paracétamol et d'AINS

Cette thèse aborde les aspects pharmacodynamiques et pharmacocinétiques d'une association de paracétamol et d'un AINS, le kétorolac. L'objectif de notre étude clinique était de comparer l'efficacité analgésique de cette combinaison avec chaque molécule seule chez 12 volontaires sains, en dessin croisé, par le biais de modèles de douleur expérimentale explorant des voies nociceptives centrales et périphériques. La combinaison s'est révélée supérieure à chaque agent seul sur le modèle périphérique de douleur, tandis qu'aucun traitement, seul ou combiné, n'a produit d'effet sur les modèles centraux. Nous avons développé une méthode d'analyse bidimensionnelle stéréosélective utilisant la chromatographie liquide couplée à la spectrométrie de masse, permettant de quantifier simultanément le paracétamol et chaque énantiomère du kétorolac. Cette méthode a permis d'exclure une interaction pharmacocinétique entre paracétamol et kétorolac. Le dernier volet de cette thèse consistait en une revue de la littérature des données traitant de la relation pharmacocinétique/pharmacodynamique (PK/PD) des analgésiques

Importance et particularités de la pharmacovigilance en pédiatrie

Les essais cliniques sont le plus souvent effectués sur une durée limitée et une population sélectionnée, excluant les enfants. Ils fournissent un premier profil de sécurité des médicaments, souvent partiel, ne mettant en évidence que les effets indésirables les plus fréquents. En pédiatrie, les phénomènes de croissance et de maturation peuvent être à l’origine de réactions aux médicaments différentes que chez l’adulte et empêchent la simple extrapolation à l’enfant des données, notamment de sécurité, obtenues chez l’adulte. La pharmacovigilance repose sur la notification spontanée des effets indésirables. Elle permet d’affiner le rapport risques/ bénéfices et d’augmenter la sécurité des médicaments une fois commercialisés. Cet article a pour but de souligner l’importance de la pharmacovigilance, en particulier dans la population pédiatrique, et de rappeler les modalités d’annonces

Dexamethasone and Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia

Comment on: COVID STEROID 2 Trial Group, Munch MW, Myatra SN, Vijayaraghavan BKT, Saseedharan S, Benfield T, Wahlin RR, Rasmussen BS, Andreasen AS, Poulsen LM, Cioccari L, Khan MS, Kapadia F, Divatia JV, Brøchner AC, Bestle MH, Helleberg M, Michelsen J, Padmanaban A, Bose N, Møller A, Borawake K, Kristiansen KT, Shukla U, Chew MS, Dixit S, Ulrik CS, Amin PR, Chawla R, Wamberg CA, Shah MS, Darfelt IS, Jørgensen VL, Smitt M, Granholm A, Kjær MN, Møller MH, Meyhoff TS, Vesterlund GK, Hammond NE, Micallef S, Bassi A, John O, Jha A, Cronhjort M, Jakob SM, Gluud C, Lange T, Kadam V, Marcussen KV, Hollenberg J, Hedman A, Nielsen H, Schjørring OL, Jensen MQ, Leistner JW, Jonassen TB, Kristensen CM, Clapp EC, Hjortsø CJS, Jensen TS, Halstad LS, Bak ERB, Zaabalawi R, Metcalf-Clausen M, Abdi S, Hatley EV, Aksnes TS, Gleipner-Andersen E, Alarcón AF, Yamin G, Heymowski A, Berggren A, La Cour K, Weihe S, Pind AH, Engstrøm J, Jha V, Venkatesh B, Perner A. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial. JAMA. 2021 Nov 9;326(18):1807-1817. doi: 10.1001/jama.2021.18295. Erratum in: JAMA. 2021 Dec 14;326(22):2333. Erratum in: JAMA. 2022 Jan 18;327(3):286. PMID: 34673895; PMCID: PMC8532039

A severe case of rhabdomyolysis after Moderna mRNA anti‐COVID‐19 vaccine with a literature review

Abstract The identification of rhabdomyolysis as a potential fatal adverse reaction to recent COVID‐19 vaccines is essential. As the symptoms of rhabdomyolysis are not specific, the threshold to actively search for this complication should be low

Practice of CYP450 genotyping and phenotyping in children in a real-life setting

Pharmacokinetics varies widely between children. Many factors play an important role in this variability, such as ontogeny, pharmacogenetics, gender, comorbidities, and drug-drug interactions. Significant work has already been done in adults to understand the impact of genetic polymorphisms on drug-metabolizing enzyme activity and drug response. Data remain poor in children due to ontogeny that impacts genotyping-phenotyping correlation and the difficulty enrolling children in prospective studies. Our study aimed to describe the use of cytochromes P450 (CYP) phenotyping and/or genotyping tests in children in a real-life setting and assess the correlation between the genotype and the phenotype. We reviewed the results of tests performed between January 2005 and December 2020. Fifty-two children were genotyped and/or phenotyped. Four patients were excluded from the present analysis as they only underwent ABCB1 genotyping, without CYP testing. Of the remainder, 18 underwent simultaneous CYP genotyping and phenotyping, while 17 underwent CYP genotyping only, and 13 underwent CYP phenotyping only. In all cases, investigations were performed after the following situations: insufficient clinical response to treatment, low plasma concentrations, and adverse drug reactions (ADR). The vast majority of cases were related to immunosuppressive or antipsychotic therapy. Genotyping and/or phenotyping explained or contributed to the aforementioned clinical events in 56% of cases. The correlation between the genotype and the phenotype showed variability depending on the assessed cytochrome. In several cases, the phenotype did not correspond to the genotype because of comedications. In conclusion, there is clearly value in guiding drug based on CYP activity in children

Applications of CYP450 Testing in the Clinical Setting

Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homozygous and heterozygous carriers of CYP2C9 variant alleles require lower doses of phenytoin to reach therapeutic plasma concentrations, and are at increased risk of toxicity. New diagnostic techniques made safer and easier should allow quicker diagnosis of metabolic variations. Genotyping and phenotyping may therefore be considered where dosing guidelines according to CYP genotype have been published, and help identify the right molecule for the right patient