Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables.

Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.

Seronegative acute encephalitis following COVID-19 vaccines: a case series of an overlooked diagnosis with literature review.

PURPOSE: Autoimmune encephalitis is a neurological emergency of new-onset altered mental status, caused by an exaggerated immune-mediated response that targets the central nervous system. Autoimmune encephalitis has become an emerging differential diagnosis, when a classical infection cannot explain neurological symptoms. Displaying overlapping clinical presentations, ranging from the insidious onset of cognitive deficiency to more severe forms of encephalopathy with refractory seizures, autoimmune encephalitis can be challenging for clinicians. When evidence of malignancy is absent and pathogenic autoantibodies are undetected, with typical clinical and imaging features of autoimmune encephalitis, seronegative autoimmune encephalitis may be considered. Recently, vaccination-related autoimmune encephalitis and acute encephalitis after COVID-19 vaccination have attracted attention. METHODS AND RESULTS: We report a case series consisting of three patients with autoimmune encephalitis occurring shortly after COVID-19 vaccination and a current review of all previous reported autoimmune encephalitis related to COVID-19 vaccines. CONCLUSION: We emphasise on the prompt diagnosis of autoimmune encephalitis induced by Covid-19 vaccines and its timely treatment to improve the clinical outcome of this severe neurological condition. Post-licencing vaccine safety surveillance for potential adverse events is essential for vaccine safety and public confidence.

Isoniazid Therapeutic Drug Monitoring in Tunisian Patients With Tuberculosis.

A regular therapeutic drug monitoring (TDM) of isoniazid could be useful to predict the acetylation profile and to prescribe doses associated with optimal efficacy and safety. We aimed to assess the usefulness of isoniazid TDM in the Tunisian population, to describe the acetylation profile distribution in this population, and to investigate the influence of certain parameters on acetylation phenotype. We performed a retrospective study including Tunisian patients with tuberculosis underwent an isoniazid TDM. Isoniazid concentrations were measured 3 hours after drug intake (C3 ). Subsequent isoniazid doses were adjusted to maintain the C3 within the recommended target (1-2 µg/mL). Patients were qualified as slow acetylators (SAs) or rapid acetylators (RAs) according to their acetylation index. Among the 255 patients, 58% were SAs and 42% were RAs. Of all patients, only 30.6% had a C3 value within the target range. A dose adjustment has been performed for patients with C3 outside the target range. C3 was controlled in 77 patients. It became within the target range in 39 patients (50.6%). The median recommended isoniazid weight doses for SAs and RAs were 2.1 ± 0.7 mg/kg and 4.2 ± 1.4 mg/kg, respectively. The multivariate analysis showed that body weight, C3, and C3 /isoniazid dose were found to be significantly different between the 2 acetylation groups. In the pediatric group, only 9 had a C3 value within the target range, and all of them were RAs. The irrevocable interest of isoniazid TDM has been shown in Tunisian patients with tuberculosis, in both adult and pediatric patients, as isoniazid demonstrates an unpredictable pharmacokinetic profile.

Meglumine antimoniate-induced DRESS: original case with a positive skin test.

We report a case of a 64-year-old woman treated with meglumine antimoniate (Glucantime®). On day 20, she developed fever, a pruriginous skin rash and myalgia. The blood tests showed eosinophilia and hepatic cytolysis. The clinico-biological picture improved gradually and the symptoms disappeared 4 weeks after the drug withdrawal. Six weeks later, intradermal tests to Glucantime® were performed and were positive at 48 hour-reading. This clinical picture suggests DRESS induced by meglumine antimoniate. To the best of our knowledge, only one case of meglumine antimoniate-induced DRESS has been reported in the literature and we are the first to report a case confirmed by skin tests.

Association of non-immediate drug hypersensitivity with drug exposure: A case control analysis of spontaneous reports from a Tunisian pharmacovigilance database.

PURPOSE: To assess delayed-type cutaneous reactions (DTCRs) related to drugs, using a case-control approach to qualify drug risks. METHODS: The study used the Tunisian pharmacovigilance database of Monastir. The association between drugs and DTCRs was assessed using a case/non-case method. Drugs were grouped according to the ATC Classification System. Patients were defined as "cases" if they have developed DTCRs regardless of the causality assessment. All other reports were "non-cases". Association between reactions and drugs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals (CIs). A p value < 0.05 was considered significant. RESULTS: The analysis was carried out on 1798 reports, of which 867 concerned DTCRs (cases) and 931 concerned non-cases. The calculated risk estimates were significant for cefotaxime (ROR 2.1; 95% CI 1.5 to 3), pristinamycin (ROR 4; 95% CI 2 to 7.9), sulfamethoxazole (ROR 4.4; 95% CI 1.6 to 11.7), oxacillin (ROR 2.2; 95% CI 1.2 to 3.8), doxycycline (ROR 10.8; 95% CI 1.4 to 84.9), carbamazepine (ROR 3.3; 95% CI 1.7 to 6.2), phenobarbital (ROR 2.3; 95% CI 1.03 to 5.1), allopurinol (ROR 3.6; 95% CI 1.8 to 7.2), furosemide (ROR 2.4; 95% CI 1.3 to 6.3), hydrochlorothiazide(ROR 2.9; 95% CI 1.3 to 6.3) and candesartan (ROR 4.7; 95% CI 1.3 to 16.6). CONCLUSION: Our findings corroborate risks for a number of drugs, such as antibacterials, antiepileptics and allopurinol in inducing DTCRs. Given the widespread use of these drug classes, awareness should be raised among patients and prescribers about these risks.