Clinical and biological assessment of lamotrigine and levetiracetam plasma assays at the Rennes University Hospital

International audienceIntroduction: Requests for lamotrigine and levetiracetam plasma assays have increased significantly since their development in the biological and forensic toxicology laboratory at the University Hospital of Rennes in 2015. The purpose of this study was to evaluate the follow-up of French National Authority for Health (HAS) guidelines for antiepileptic drug assays and the impact of assay results on medical management.Methods: Two hundred and forty-two assay results of these two antiepileptics for 169 patients hospitalized in different care wards between 2015 and 2018 were retrospectively analyzed.Results: The mean age of the study population was 50.3±25.4 years. Of the 207 assays prescribed for epilepsy, 177 (85.5%) were in line with the 2007 HAS guidelines, namely: 76/177 (42.9%) for therapeutic adjustment in the event of seizure recurrence or aggravation; 45/177 (25.4%) for specific clinical situations; 23/177 (13%) for proven or suspected poor compliance; 23/177 (13%) for suspected overdose; 8/177 (4.5%) following initiation of treatment; and 2/177 (1.1%) for drug interaction management. Thirty of the 207 assays (14.5%) were thus inappropriate. No significant differences were found regarding the hospitalization frequency after a visit to the emergency room (P=0.9) between patients with lamotrigine and/or levetiracetam plasma assays in therapeutic ranges versus those with concentrations outside the therapeutic ranges. Dosage changes were more frequent in patients with assays in therapeutic ranges compared to patients with plasma assays outside the therapeutic ranges (P=0.0015), suggesting a treatment reassessment primarily based on clinical criteria.Conclusion: The analysis of requests for antiepileptic drug assays at the University Hospital of Rennes revealed that clinicians were well aware of the HAS guidelines. In addition, the assay results were mainly consistent with clinical intuition, suggesting a real added value for patient management. However, the consequences in terms of changes in medical care seem limited. This assessment illustrates the importance of strengthening the dialogue between pharmacists, biologists and clinicians

Molecular networking for drug toxicities studies: The case of hydroxychloroquine in covid-19 patients

International audienceUsing drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient’s plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Modification de la perception des sons sous antiépileptiques : une revue de la littérature et des bases de pharmacovigilance

National audiencePitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis