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.

Pharmacokinetics of Imatinib Mesylate and Development of Limited Sampling Strategies for Estimating the Area under the Concentration-Time Curve of Imatinib Mesylate in Palestinian Patients with Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: Imatinib is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). The area under the concentration-time curve (AUC) is a pharmacokinetic parameter that symbolizes overall exposure to a drug, which is correlated with complete cytogenetic and treatment responses to imatinib, as well as its side effects in patients with CML. The limited sampling strategy (LSS) is considered a sufficiently precise and practical method that can be used to estimate pharmacokinetic parameters such as AUC, without the need for frequent, costly, and inconvenient blood sampling. This study aims to investigate the pharmacokinetic parameters of imatinib, develop and validate a reliable and practical LSS for estimating imatinib AUC0-24, and determine the optimum sampling points for predicting the imatinib AUC after the administration of once-daily imatinib in Palestinian patients with CML. METHOD: Pharmacokinetic profiles, involving six blood samples collected during a 24-h dosing interval, were obtained from 25 Palestinian patients diagnosed with CML who had been receiving imatinib for at least 7 days and had reached a steady-state level. Imatinib AUC0-24 was calculated using the trapezoidal rule, and linear regression analysis was performed to assess the relationship between measured AUC0-24 and concentrations at each sampling time. All developed models were analyzed to determine their effectiveness in predicting AUC0-24 and to identify the optimal sampling time. To evaluate predictive performance, two error indices were employed: the percentage of root mean squared error (% RMSE) and the mean predictive error (% MPE). Bland and Altman plots, along with mountain plots, were utilized to assess the agreement between measured and predicted AUC. RESULTS: Among the one-timepoint estimations, predicted AUC0-24 based on concentration of imatinib at the eighth hour after administration (C8-predicted AUC0-24) demonstrated the highest correlation with the measured AUC (r2 = 0.97, % RMSE = 6.3). In two-timepoint estimations, the model consisting of C0 and C8 yielded the highest correlation between predicted and measured imatinib AUC (r2 = 0.993 and % RMSE = 3.0). In three-timepoint estimations, the combination of C0, C1, and C8 provided the most robust multilinear regression for predicting imatinib AUC0-24 (r2 = 0.996, % RMSE = 2.2). This combination also outperformed all other models in predicting AUC. The use of a two-timepoint limited sampling strategy (LSS) for predicting AUC was found to be reliable and practical. While C0/C8 exhibited the highest correlation, the use of C0/C4 could be a more practical and equally accurate choice. Therapeutic drug monitoring of imatinib based on C0 can also be employed in routine clinical practice owing to its reliability and practicality. CONCLUSION: The LSS using one timepoint, especially C0, can effectively predict imatinib AUC. This approach offers practical benefits in optimizing dose regimens and improving adherence. However, for more precise estimation of imatinib AUC, utilizing two- or three-timepoint concentrations is recommended over relying on a single point.

Drug reaction with eosinophilia and systemic symptoms in a paediatric population: Interest of skin tests.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction. It is uncommon in the paediatric population and can be difficult to diagnose as its initial symptoms may mimic a viral infection. OBJECTIVE: To analyse the features of paediatric DRESS and to evaluate the interest of skin tests in identifying the causative drugs. METHODS: It is a retrospective analysis (2004-2021) of DRESS cases diagnosed in paediatric patients. The DRESS diagnosis was defined using the RegiSCAR scoring. The skin tests were performed according to the ENDA recommendations. RESULTS: We included 19 cases of DRESS occurred in 18 patients. Common clinical symptoms were exanthema and fever in 94.7% of cases each. The most commonly affected organ was the liver (84.2%). Among the implicated drugs, 16 were tested and skin tests were positive in 75%. To assess cross-reactivity and co-sensitization, skin tests with related and/or co-administered drugs were performed in eight patients. Among them, only one child had positive results. CONCLUSION: Early diagnosis of DRESS and discontinuation of the incriminated drug might reduce the incidence of mortality in the paediatric population. Skin tests could be a safe and useful tool to identify the causative drug and assess cross-reactivity.

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.

Development of Limited Sampling Strategies for the Estimation of Tacrolimus Area Under the Curve in Adult Kidney Transplant Recipients According to the Posttransplantation Time.

BACKGROUND: Limited sampling strategies (LSS), using few sampling times after dosing, have been used to reliably predict tacrolimus area under the 12-hour concentration-time curve (AUC). Because the pharmacokinetics of tacrolimus is subject to significant changes over the exposure time to this drug, it can be hypothesized that the reliability of the LSS would also change. This study aimed to develop a reliable and practical LSS allowing the estimation of tacrolimus AUC in Tunisian kidney transplant recipients taking into account the posttransplantation time. METHODS: Thirty Tunisian patients were enrolled into 3 groups (10 in each group) according to the posttransplantation period: period 1: between 1 day and 3 months, period 2: between 3 and 12 months and period 3 over 12 months, as defined by the European consensus conference on the therapeutic drug monitoring of tacrolimus. Samples were collected just before and 0.5, 1, 2, 4, 6, 8, and 12 hours after tacrolimus administration. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Error indices (mean absolute prediction error and the root mean squared prediction error) were used to evaluate the predictive performance. RESULTS: Among the 1-point estimations, the C4-predicted AUC showed the highest correlation with the measured one during period 1 and period 2 (r = 0.94 and 0.91, respectively) but not period 3 (r = 0.76). The C0-predicted and the measured AUC become less and less correlated from period 1 to period 3 (r = 0.81, 0.75, and 0.66), respectively. Only the model including the C0/C2 provided a high correlation between predicted and measured tacrolimus AUC regardless of the posttransplant period (r = 0.95, 0.96, 0.98 and root mean squared prediction error = 4.1, 5.8, 4.2 during periods 1, 2, and 3, respectively). CONCLUSIONS: Our data clearly indicate that the predictive performance of LSS is prone to change according to the posttransplantation time. A 2-time point LSS was found to be sufficient to predict tacrolimus AUC. The LSS using C0 and C2 is reliable, accurate, and practical to estimate the AUC of tacrolimus regardless of the posttransplantation time.

Role of HLA-G 14bp deletion/insertion and +3142C>G polymorphisms in the production of sHLA-G molecules in relapsing-remitting multiple sclerosis.

HLA-G is believed to act as an anti-inflammatory molecule in Multiple Sclerosis (MS). The 3' untranslated region of the HLA-G gene is characterized by two polymorphisms, DEL/INS14bp and +3142C>G, which control soluble HLA-G (sHLA-G) production. The influence of these two HLA-G variants on sHLA-G serum and cerebrospinal fluid (CSF) levels was investigated in 69 Relapsing-Remitting MS patients grouped in magnetic resonance imaging (MRI) inactive and active disease. Serum and CSF sHLA-G levels were more elevated in high than in low DEL/INS 14bp and +3142C>G sHLA-G producers and were different among the various combined HLA-G genotypes in both MRI inactive and active diseases. The highest and the lowest sHLA-G values were identified in MS patients with C/C,DEL/DEL and G/G,INS/INS genotypes, respectively. Our preliminary findings suggest that serum and CSF sHLA-G levels in MS could be influenced by HLA-G polymorphisms irrespective of the inflammatory microenvironment.

[Not Available]. / Les vaccins anti A(H1N1) en Tunisie : efficacité et tolérance.

OBJECTIVE: We carried out this study in order to evaluate the effectiveness and the safety of the two H1N1 vaccines available in Tunisia: Focetria® and Panenza®. METHODS: It's a prospective epidemiological study including 601 vaccinated subjects. The vaccine effectiveness was based on the occurrence of flu clinical symptoms after vaccination. The safety was based on the occurrence of unexpected events after vaccines administration. The vaccines imputability was established according to Begaud et al. RESULTS: The number of subjects vaccinated by Focetria® is more important than Panenza®. The efficiency of vaccines would be 93.6%. Neither the medical statue nor the type of the vaccine used influence the occurrence of a flu episode after vaccination. We recorded 406 adverse effects (32.4%) with a high score of imputability (I3). Focetria® adverse effects were more frequent than Panenza® ones (p=0.009). Almost all adverse events disappeared within few days. CONCLUSION: The two vaccines used in Tunisia remain enough efficient to face the influenza (H1N1) pandemia and are well tolerated independently of the demographic and pathological statue of the vaccinated person as well as nature of the vaccine used.

Molecular analysis of HBV genotypes and subgenotypes in the Central-East region of Tunisia.

BACKGROUND: In Tunisia, country of intermediate endemicity for Hepatitis B virus (HBV) infection, most molecular studies on the virus have been carried out in the North of the country and little is known about other regions. The aim of this study was to determine HBV genotype and subgenotypes in Central-East Tunisia. A total of 217 HBs antigen positive patients were enrolled and determination of genotype was investigated in 130 patients with detectable HBV DNA. HBV genotyping methods were: PCR-RFLP on the pre-S region, a PCR using type-specific primers in the S region (TSP-PCR) and partial sequencing in the pre-S region. RESULTS: Three genotypes (D, B and A) were detected by the PCR-RFLP method and two (D and A) with the TSP-PCR method, the concordance between the two methods was 93%. Sequencing and phylogenetic analysis of 32 strains, retrieved the same genotype (D and A) for samples with concordant results and genotype D for samples with discordant results. The sequences of discordant genotypes had a restriction site in the pre-S gene which led to erroneous result by the PCR-RFLP method. Thus, prevalence of genotype D and A was 96% and 4%, respectively. Phylogenetic analysis showed the predominance of two subgenotypes D1 (55%) and D7 (41%). Only one strain clustered with D3 subgenotype (3%). CONCLUSIONS: Predominance of subgenotype D7 appears to occur in northern regions of Africa with transition to subgenotype D1 in the East of the continent. HBV genetic variability may lead to wrong results in rapid genotyping methods and sequence analysis is needed to clarify atypical results.

Amoxicillin-Induced Hypersensitivity After DRESS To Carbamazepine.

The anticonvulsant hypersensitivity syndrome, also known as drug rash eosinophilia and systemic symptoms (DRESS), is a rare but severe form of adverse cutaneous reaction. Several aromatic anticonvulsant drugs, such as carbamazepine (CBZ), phenytoin, or phenobarbital have been frequently associated with the onset of DRESS. Cross-reactivity among the aromatic anticonvulsants frequently occurs (40 to 80% of patients). However, cross reactivity with other drugs such as betalactams have exceptionally been reported. We report a clinical observation describing a DRESS associated with CBZ with a subsequent hypersensitivity to amoxicillin (AMX). A 34-year-old male with a 20-year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, CBZ was added. Thirty-four days later, the patient developed hyperthermia (39.5°C), cervical lymphadenopathy, and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of (16.1 × 103/µL, 17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). CBZ was discontinued. One month later, all the symptoms were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48-hour reading. About 2 years later, the patient exhibited an extensive pruritic skin rash, 2 days after AMX intake. Laboratory exams showed eosinophilia (7%) but neither elevated liver enzymes nor renal dysfunction. All these symptoms have disappeared 5 days after AMX withdrawal. Intradermal test to AMX was positive but not to other betalactams. Throughout this clinical observation, we report a CBZ-induced DRESS and describe the possibility of cross reactivity between CBZ and AMX. This cross reactivity was observed despite the lack of chemical similarity between both drugs.

[Not Available]. / DRESS syndrome : étude de 11 cas et revue de la littérature.

AIM: Study the epidemiological, clinical, biological and chronological drug rash with eosinophilia and systemic symptoms (DRESS) characteristic and indicate the implicated drugs. METHODS: We carried a retrospective study including all DRESS cases notified to the Pharmacovigilance Unit of Monastir. RESULTS: Our cohort of eleven patients had a median age of 40 years. Clinical examination revealed skin eruption and fever among all patients. Laboratory findings showed marked eosinophilia among all patients, hepatic cytolysis among eight patients and creatinin serum level increase among four patients. An interstitial pulmonary syndrome was noted among two patients. After culprit-drug withdrawal, outcomes were favorable for all patients. Skin tests were positive with carbamazepin and cefotaxim and negative with sulfasalazine, allopurinol and terbinafine. CONCLUSION: Throughout this paper, we point out the contribution of skin tests to identify implicated drug in inducing DRESS and to testify cross reactivity and we point out the possibility of neosensitisation to a non related chemical drug after DRESS syndrome.