While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports ...of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 interquartile range: 10; 23 days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.
The extent of sotalol‐induced QTc prolongation on the electrocardiogram, is variable among subjects and influenced by sex. However, the influence of baseline QTc on the extent of drug‐induced QTc ...prolongation remains unclear. This was studied around peak plasma concentration in a large cohort of 376 healthy male and 614 healthy female subjects who received 80 mg of sotalol orally. Baseline QTc was 379 ± 16 ms in men and 393 ± 15 ms in women (P < .0001). The change in QTc from baseline was highly variable among both sexes and was greater in women than in men (26.5 ± 13.2 vs.13.0 ± 10.8 ms; P < .0001). The slope of the regression line between QTc on sotalol and baseline QTc did not significantly differ from unity in men and in women, indicating that the extent of QTc prolongation with sotalol was not influenced by baseline QTc. Assessing QTc after administration of an IKr blocker may be more important than measuring a baseline QTc.
Aims
Drug‐induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify ...suspected drugs.
Methods
Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All cases were initially analysed according to the French imputability method by institutional pharmacologists (clinicians or pharmacists). Further analyses of well documented cases were then performed.
Results
In this study, 329 cases of aseptic meningitis were retrieved from the French Pharmacovigilance Database for a total of 429 suspected drugs. Analysis of 203 well documented cases, including 282 drugs, showed that the main reported classes were intravenous polyvalent immunoglobulin, nonsteroidal anti‐inflammatory drugs (NSAIDs), vaccines, antimicrobials, intrathecal antimetabolites, corticosteroids and antalgics/anaesthetics (except NSAIDs). Lymphocytic (33.0%) and purulent (44.8%) meningitis represented the majority of cases of aseptic meningitis. In other cases, the cerebrospinal fluid was mixed (45–55% of neutrophils +45–55% of lymphocytes) or data about cerebrospinal fluid composition were lacking. Most DIAM cases (96%) had a favourable reported outcome with full recovery or minimal residual symptoms.
Conclusion
The most frequently involved drugs in DIAM were intravenous polyvalent immunoglobulin, NSAIDs, vaccines, and antimicrobials and this without being able to differentiate them in terms of biological characteristics. Although further studies are needed to better understand the pathophysiological mechanisms of DIAM, a continuous enrichment of pharmacovigilance databases is essential to identify new signals and to help clinicians in the understanding of DIAM.
A large number of drugs can induce prolongation of cardiac repolarization and life-threatening cardiac arrhythmias. The prediction of this side effect is however challenging as it usually develops in ...some genetically predisposed individuals with normal cardiac repolarization at baseline. Here, we describe a platform based on a genetically diverse panel of induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop a cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting in vivo with extremely low or high changes in cardiac repolarization in response to a pharmacological challenge with sotalol. In vitro, the responses to sotalol were highly variable but strongly correlated to the inter-individual differences observed in vivo. Transcriptomic profiling identified dysregulation of genes (
,
) involved in downstream regulation of cardiac repolarization machinery as underlying high sensitivity to sotalol. Our findings offer novel insights for the development of iPSC-based screening assays for testing individual drug reactions.
Summary Background Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The ...frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 ( CYP2C19 ) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. Methods Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. Findings Median clopidogrel exposure time was 1·07 years (IQR 0·28–3·0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio HR 3·69 95% CI 1·69–8·05, p=0·0005), as did stent thrombosis (eight vs four events; HR 6·02 1·81–20·04, p=0·0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3·00 1·27–7·10, p=0·009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4·04 1·81–9·02, p=0·0006). Interpretation The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction. Funding Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris.
Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted ...therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score.
Aims
We investigated the effect of gadopiclenol, a new gadolinium‐based contrast agent, on the QTc interval at clinical and supraclinical dose, considering the relative hyperosmolarity of this ...product.
Methods
This was a single centre, randomized, double‐blind, placebo‐ and positive‐controlled, 4‐way crossover study. Forty‐eight healthy male and female subjects were included to receive single intravenous (i.v.) administrations of gadopiclenol at the clinical dose of 0.1 mmol kg−1, standard for current gadolinium‐based contrast agents, the supraclinical dose of 0.3 mmol kg−1, placebo and a single oral dose of 400 mg moxifloxacin.
Results
The largest time‐matched placebo‐corrected, mean change from‐baseline in QTcF (ΔΔQTcF) was observed 3 hours after administration of 0.1 mmol kg−1 gadopiclenol (2.39 ms, 90% confidence interval CI: 0.35, 4.43 ms) and 5 minutes after administration of 0.3 mmol kg−1 (4.81 ms, 90%CI: 2.84, 6.78 ms). The upper limit of the 90% CI was under the threshold of 10 ms, demonstrating no significant effect of gadopiclenol on QTc interval. From 1.5 to 4 hours postdose moxifloxacin, the lower limit of the 90% CI of ΔΔQTcF exceeded 5 ms demonstrating assay sensitivity. Although there was a positive slope, the concentration–response analysis estimated that the values of ΔΔQTcF at the maximal concentration of gadopiclenol at 0.1 and 0.3 mmol kg−1 were 0.41 and 2.23 ms, respectively, with the upper limit of the 90% CI not exceeding 10 ms. No serious or severe adverse events or treatment discontinuations due to adverse events were reported.
Conclusion
This thorough QT/QTc study demonstrated that gadopiclenol did not prolong the QT interval at clinical and supraclinical doses and was well tolerated in healthy volunteers. The positive slope of the QTc prolongation vs concentration relationship suggests that hyperosmolarity could be associated with QTc prolongation. However, the amplitude of this effects is unlikely to be associated with proarrhythmia.
QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than ...men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle-stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration.
Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in ...transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other immunosuppressive agents. This article reviews the adverse effects of mTOR inhibitors in solid organ transplantation, with special attention given to mechanisms hypothesized to cause adverse events and their management strategies.
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