[Management of immune-related toxicities associated with immune checkpoints inhibitors: Data from the multidisciplinary meeting « ToxImmun ¼ in Eastern Occitania]. / Gestion des toxicités induites par les inhibiteurs de checkpoint immunologique : données de la réunion de concertation pluridisciplinaire « ToxImmun ¼ en Occitanie Est.

Immune checkpoint inhibitors (ICIs) can cause numerous and complex immune-related adverse events whose management need a multidisciplinary approach. Herein, we investigated 114 requests, mostly concerning patients suffering from lung cancer, that were submitted to the « ToxImmun ¼ multidisciplinary meeting in Eastern Occitania between December the 17th 2018 and January the 20th 2020. The leading reasons for the request concerned the putative causal link between immunotherapy and immune-toxicity and its management, followed by possible retreatment after temporary withdrawn because of adverse event, and finally the possibility to initiate ICIs in patients with pre-existing autoimmunity. Colitis, hepatitis and myocarditis were the most frequent immune-related adverse events (IRAEs), both all grade and grade 3-4. Sicca syndrome (with or without Sjogren criteria) was also frequent (26% of cases) and seems to be associated with severe toxicity and multi-toxicity. The mean time to first IRAE was 3.8 months, a time shortened with the use of anti-PD-L1 agents or ICI combination. A majority of requests came from initial evaluation by the internist confirming the early and main role of this specialty in the management of immunotoxicity. Expansion of this regional multidisciplinary meeting, coordinated by internists and medical oncologists, could improve management of immune-related adverse events for the patients' benefits.

Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database.

BACKGROUND: Inhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed. OBJECTIVES: To detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study. METHODS: All spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case-noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period. RESULTS: Among 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1-96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9-340·9), sitagliptin (ROR 17·0, 95% CI 8·9-32·5) and saxagliptin (ROR 16·5, 95% CI 2·3-119·1). Analyses adjusted on dispensing data led to similar results. CONCLUSIONS: These data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.

[Drug-induced pancreatitis. A review of French spontaneous reports]. / Pancréatites d'origine médicamenteuse. Revue des notifications spontanées en France.

PURPOSE: Identify the main pharmacological classes inducing pancreatitis using spontaneous reports recorded in the French pharmacovigilance database (FPVD). METHODS: Cases of pancreatitis recorded in FPVD between January 1st 1985 and December 31st 2013 were selected using the 2001 consensus conference criteria of the French High Health Authority. RESULTS: During this period, 2975 observations were selected with 1151 fulfilling criteria of drug-induced pancreatitis (i.e. 0.22% of total notifications in the FPVD). According to ATC classification, the pharmacological classes most frequently found were antiretroviral, analgesic, lipid-lowering, immunosuppressive and insulin secreting drugs. For some drugs (metformin, omeprazole, etc.) pancreatitis was "unlabelled" in the summary of product characteristics. CONCLUSION: This review allows to identify the main drug classes currently involved in spontaneous reporting of pancreatitis in France.

[Appropriate medication prescribing in older people]. / Bon usage des médicaments chez le sujet âgé.

Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.

Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins.

The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complex I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro.

Therapeutic drug monitoring of posaconazole in hematology adults under posaconazole prophylaxis: influence of food intake.

Posaconazole (PCZ) is given at 200 mg three times daily as a fungal prophylaxis in neutropenic hematologic malignancy patients. A relationship between exposure, plasma concentration, and efficacy is suggested. The objectives of this prospective study were to analyze the PCZ plasma concentration in hematology adults at high risk of developing invasive fungal infections (IFIs), and factors that could have an impact on the PCZ plasma concentration. PCZ plasma concentrations were measured after 2, 7, 10, 14, and 21 days of PCZ prophylaxis. Factors such as gender, age, body weight, posology, treatment duration, mucositis, proton pump inhibitor (PPI) use, and food intake were studied. Sixty-three patients were included, with a median age of 52 years (range 17-70) and a median weight of 75 kg (range 47-150). The median PCZ plasma concentration of the 63 patients ranged from 0.42 to 0.48 mg/L. At day 2, 30% of PCZ plasma concentration were under 0.35 mg/L, and at day 7, 74% were <0.70 mg/L. PCZ plasma concentrations were not affected by gender, age, body weight, or treatment duration. We found that food intake had a high influence on PCZ plasma concentrations (p = 0.0049). PCZ was well tolerated. One patient has developed a probable IFI, probably related to a low exposure to PCZ. PCZ therapeutic drug monitoring (TDM) is essential in order to early detect patients with low concentrations, to assess the etiology of such results, and to decide on the treatment strategy to apply.

Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value?

WHAT IS KNOWN AND OBJECTIVE: In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL. METHODS: Relapsed patients and subjects in EFS were compared for MTX serum concentrations 24, 36, 48 and 72 h after the start of 24 h infusion. Clearance (Cl), area under the curve (AUC) and volume of distribution (V(d) ) of the drug were estimated by the NONMEM computer program and also compared between both groups. RESULTS AND DISCUSSION: Among 69 children included, 54 (78·3%) were still in EFS, whereas 15 (21·7%) relapsed. The difference between relapsed and EFS patients for the pharmacokinetic parameters studied was not significant. On the contrary, the cohort studied was representative and known prognostic factors for relapse in ALL were significantly associated with relapse. WHAT IS NEW AND CONCLUSION: Serum concentrations and pharmacokinetic parameters of MTX are not associated with outcome in ALL. Prognoses based on single-drug pharmacokinetic estimates within a complex multiple-agent protocol appear to be unreliable. However, therapeutic drug monitoring of high-dose methotrexate remains a useful tool for early detection of impaired elimination and for avoiding systemic toxicity.

Antipsychotics-induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database.

PURPOSE: First- and second-generation antipsychotics commonly cause mild gastrointestinal hypomotility. Intestinal necrosis may be a consequence of such gastrointestinal perturbations. MATERIAL AND METHODS: We reviewed all the observations of ischaemic colitis and gastrointestinal necrosis notified to the French Pharmacovigilance database (FPD) between 1997 and the end of 2006. RESULTS: Thirty-eight cases of ischaemic colitis and gastrointestinal necrosis associated with antipsychotics were analysed. The average age of the patients was 42.7 +/- 14.7 years (15-77 years). The digestive complication was an intestinal necrosis in 27 cases, an ischaemic colitis in 10 cases (with perforation in three cases), and one perforation. Surgical procedure (partial or total resection of the colon and/or small intestine) was performed in 24 patients. Six patients died despite surgery. Among the whole population, the outcome was fatal in 14 patients, 13 patients recovered with sequelae, six patients fully recovered, and the outcome remained unknown in five cases.In 55.2% of the cases, the patients were treated with more than one antipsychotic medication. The most frequently involved antipsychotics were: clozapine, levomepromazine, cyamemazine, haloperidol. Associated antimuscarinic drugs (excluding antipsychotics) were found in 68.4% of patients. DISCUSSION/CONCLUSION: Intestinal necrosis associated with antipsychotics is very rare; however mortality is high, with a rapid worsening of patients towards septic shock in spite of mild clinical symptoms. It is therefore essential to monitor the patients receiving antipsychotics especially when they are prescribed concomitant medications. The occurrence of non-specific clinical symptoms such as abdominal pain associated with vomiting and/or diarrhea should draw attention.

[Carbamazepine and clarithromycin: a clinically relevant drug interaction]. / Carbamazépine et clarithromycine: une interaction médicamenteuse cliniquement significative.

BACKGROUND: Carbamazepine is associated with clinically relevant drug interactions especially with macrolide antibiotics such as troleandomycin and erythromycin. These drugs inhibit the metabolism of carbamazepine. Clarithromycin, a macrolide antibiotic similar to erythromycin, is widely used to treat respiratory tract infections and is used for the treatment of atypical mycobacterial infections and Helicobacter pylori-associated peptic ulcer disease. METHODS: To report an interaction between carbamazepine and clarithromycin, we present a study that includes three regular attenders at the epilepsy department of Montpellier and seven cases reported by the French national drug safety center. RESULTS: In patients receiving carbamazepine alone or in combination with other drugs, administration of clarithromycin led to a transitory overdosage (ataxia, dizziness, diplopia, nausea, vomiting, drowsiness). Blood level was available in 8 patients with a concentration of carbamazepine ranging from 13.3 to 28.5 mg/l. CONCLUSION: Carbamazepine is extensively metabolized by cytochrome P450 enzymes, especially CYP34A. As clarithromycin is also metabolized by CYP3A4, this drug has the propensity to inhibit the metabolism of carbamazepine. Clarithromycin should be thus avoided in patients taking carbamazepine.

Erythema nodosum and glatiramer acetate treatment in relapsing-remitting multiple sclerosis.

Glatiramer acetate (GA), a well tolerated immunomodulatory treatment for relapsing-remitting multiple sclerosis (RR-MS), consists of a 4-amino acid polymer that mimics the myelin basic protein (MBP). We report the first case of biopsy-proven erythema nodosum (EN) in a patient presenting RR-MS under GA treatment. Comprehensive exams were negative in the search of the etiology of EN, which spontaneously resolved despite treatment continuation. GA treatment is known to generate reactive polyclonal antibodies that can cross-react with myelin epitopes, like MBP. These antibodies may also be implicated in allergenic reactions and auto-immune adverse events, such as anaphylactic shock, lymphadenopathy, livedo-like dermatitis, or lymphocytic infiltration. EN is an unspecific skin reaction occurring in several disorders and induced by many treatments. As EN can result from a polyclonal antibody response or type I hypersensitivity mechanisms, we hypothesize that GA treatment could be responsible for the occurrence of EN.

Inherited long QT syndrome revealed by antifungals drug-drug interaction.

A 14-year-old Tahitian girl with acute myeloid leukaemia and a suspected mucormucosis infection was treated with intravenous voriconazole and caspofungin. Because of worsening of fungal infection, voriconazole was switched to posaconazole. During the switch, the patient presented with QT interval prolongation with 'torsades de pointes' and reversible cardiac arrest. Voriconazole plasma level measured 15 h after the last administration was 7 mg/L. Genotyping suggested that the patient was an extensive metabolizer with respect to CYP2C9 and CYP2C19. The association of antifungal agents with pro-arrhythmogenic drugs and other risk factors led to torsades de pointes and the revealing of inherited QT syndrome.

Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?

OBJECTIVE: To improve the definition of the various clinical patterns of patients with drug-induced cutaneous side-effects with systemic symptoms, and their possible relationships with the triggering medication, with the ultimate goal of helping in the identification of the causal drug in difficult situations when the patient is taking several drugs. METHODS: Cases of drug-induced cutaneous side-effects associated with various systemic syndromes related to anticonvulsants (carbamazepine, phenytoin and phenobarbitone), minocycline, allopurinol, abacavir and nevirapine were collected retrospectively from the French Pharmacovigilance database (FPD) over a period of 15 years (1985-2000). The clinical patterns typical of the causative drugs were described and compared with data from the literature. RESULTS: Two hundred and sixteen patients with symptoms and signs consistent with cutaneous drug reactions with systemic symptoms were reported to the FPD during this period of time. Their pattern was similar to published data for these drugs, with fever, cutaneous eruption, hepatic abnormalities and eosinophilia being the most prominent but inconstant symptoms. There are clues suggesting that some particular lesional patterns may exist for some drugs. CONCLUSIONS: Although some trends emerge from these retrospective data, they suggest that no clear, unified outline can currently be defined for these multi-organ drug-induced reactions. Instead, a constellation of various symptoms and signs were recorded, that might be sorted in different patterns according to the causal drug, a finding that might indeed improve accurate identification of the causative drug in patients receiving several principal medications at a time. A national prospective study systematically collecting standardized data is required better to define the outlines of these severe adverse drug reactions and to evaluate prognostic data.

[Digoxin-Josamycin: a dangerous drug interaction in children]. / Digoxine-Josamycine: une interaction dangereuse chez l'enfant.

Digitalis intoxication is usually accidental in children. We report the case of a young infant with congenital heart disease in whom the coadministration of digoxin and josamycin led to a 50% increase in the digoxin concentration, generating sinoatrial block and cardiac failure. Clinical and electrocardiographic symptoms very quickly resolved following immunotherapy with antidigitalis Fab fragments. Digoxin concentrations must be carefully monitored in patients concomitantly receiving macrolides to ensure that the digoxin dose can be readjusted if necessary.

[Leflunomide-related severe axonal neuropathy]. / Neuropathie axonale sévère et léflunomide.

INTRODUCTION: Leflunomide is a new drug for the treatment of rheumatoid arthritis. Its mechanism of action is based on lymphocyte inhibition. We report the cases of two patients treated with leflunomide who developed severe sensory-motor axonal polyneuropathy. OBSERVATION: Two women (61- and 70-year-old) presented with a sensory-motor axonal polyneuropathy beginning 5 months after onset of leflunomide treatment. Etiologic investigations were negative. The symptoms rapidly improved after withdrawing leflunomide. DISCUSSION: The analysis of drug watch data found twelve patients with leflunomide-related neuropathy. Ten of them were more than 60 years old. The mean delay for onset of neuropathy was 9 months. The neuropathy improved after treatment withdrawal in seven patients. CONCLUSION: We consider these data strongly suggest that leflunomide is a cause of axonal sensory-motor neuropathy. The prevalence of such adverse events is still unknown.

Performance analysis of a rapid HPLC determination with the solvent demixing extraction of HIV antiproteases and efavirenz in plasma.

A rapid and simple high-performance liquid chromatographic method without internal standardization is evaluated for the drug-level monitoring of most marketed antiproteases and efavirenz. Following plasma deproteinization with acetonitrile, the analytes are extracted into the solvent while it is demixed by the addition of a saturating amount of neutral salt. The organic supernatant is diluted by half with water up to the polarity of the mobile phase before being injected. The isocratic mobile phase is unbuffered water-acetonitrile (52:48), and the stationary phase is LiChrospher 100 RP-8 (5 microm). Analytes are eluted between 4 min (amprenavir and indinavir) and 20 min (nelfinavir). A spreadsheet program including analysis of variance (ANOVA) and regression is used for both the overall validation of milligrams-per-liter determinations and the performance evaluation of analytical steps from chromatographic raw data. Extraction shows acceptable 5% repeatability and nearly 100% recovery, although it is somewhat concentration-dependent. The calibration function is better fitted by bilogarithmic than arithmetical regression, and the ANOVA of raw data is found quite predictive of the quality of the final determinations.