Indirect comparison of capmatinib treatment from GEOMETRY mono-1 trial to SOC in German patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations.

BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.

Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND AND OBJECTIVES: Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references. METHODS: A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug. RESULTS: Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26]. CONCLUSION: Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Toxicity burden patterns of MET-selective tyrosine kinase inhibitors: evidence from real-world pharmacovigilance.

MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib.

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Antiviral influenza treatments and hemorrhage-related adverse events in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.

STUDY OBJECTIVE: To determine whether there is a signal for gastrointestinal (GI) or intracranial (IC) hemorrhage associated with the use of antiviral medications for influenza in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. DESIGN: Disproportionality analysis. DATA SOURCE: The FAERS database was searched using OpenVigil 2.1 to identify GI and IC hemorrhage events reported between 2004 and 2022. MEASUREMENTS: Antiviral medications for influenza included the following: oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Hemorrhage events were identified using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries for GI and IC hemorrhages. Reporting odds ratios (RORs) were calculated to compare the occurrence of GI and IC hemorrhage events between antiviral drugs for influenza and (i) all other medications and (ii) antibiotics. RORs were also calculated for each of the individual antiviral medications. MAIN RESULTS: A total of 245 cases of GI hemorrhage and 23 cases of IC hemorrhage were identified in association with four antivirals. In comparison with all other drugs, the RORs of GI hemorrhage for oseltamivir, zanamivir, peramivir, baloxavir, and all antivirals combined were 1.17, 0.62, 4.44, 2.53, and 1.22, respectively, indicating potential variations in GI hemorrhage risk among the antivirals. In contrast, in comparison with all other drugs, the RORs of IC hemorrhage for oseltamivir (0.44), zanamivir (0.16), baloxavir (0.44), and all antivirals combined (0.41) were less than 1.0 which is consistent with no elevated risk of IC hemorrhage. CONCLUSION: In this study, some signals for GI hemorrhage were observed, particularly for peramivir and baloxavir marboxil. Further investigation is warranted to better understand and evaluate the potential risks of GI hemorrhage associated with antiviral treatments for influenza.

Absence of cross-toxicity between MET inhibitors in a non-small-cell lung cancer with a MET exon 14 skipping mutation.

INTRODUCTION: Selective tyrosine kinase inhibitors are proven effective in patients with non-small lung cancer (NSCLC) with a MET exon 14 skipping mutation. CASE PRESENTATION: The patient developed a metastatic lung adenocarcinoma with a MET exon 14 skipping mutation. She was treated with a first 1b MET inhibitor, Capmatinib, but had to stop the drug because of major hepatotoxicity. A few months later, she started Tepotinib, another 1b MET inhibitor with this time, no sign of hepatotoxicity. DISCUSSION: Adverse events are frequent with 1b MET inhibitors. However, there is a wide interpatient variability. Absence of cross-toxicity between Capmatinib and Tepotinib is misunderstood but can be explained by slight differences in phamarcodynamics and pharmacokinetics. Practitionners have to be warned about severe adverse events to stop or change the drug if necessary. CONCLUSION: This is the first case showing the absence of cross-toxicity between 1b MET inhibitors.

Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials.

ABSTRACT: Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 of 643 (10.4%) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (13/74 [17.6%] and 2/93 [2.2%]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range, 4-129). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3 to 5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. These trials were registered at www.ClinicalTrials.gov as # NCT01915498, NCT02577406, NCT02677922, and NCT02632708.

Anticonvulsant Agents for Treatment of Restless Legs Syndrome: A Case Report With Lamotrigine and a Review of the Literature.

INTRODUCTION: Restless Legs Syndrome (RLS) is a neurological disorder primarily treated with pregabalin and gabapentin, followed by dopamine agonists later in the process due to the risk of augmenting RLS symptoms. In addition, clinical reports have disclosed varying degrees of success employing other agents in patients unresponsive to traditional agents. Here, we present a patient who had success in the reduction of RLS symptoms with lamotrigine, a broad-spectrum anticonvulsant. Previously, lamotrigine had been used in 2 trials with successful treatment of RLS. CASE REPORT: We present a 58-year-old right-handed lady with long-standing history of smoking, hypertension, dyslipidaemia, prediabetes, gastro-esophageal reflux disease, asthma, strabismus, uterine cancer, severe and debilitating course of RLS accompanied by unexplained deterioration. The patient initially demonstrated abnormal sensation in all her limbs, which worsened with radiotherapy treatment, and was eventually diagnosed with RLS based on the diagnostic criteria. Subsequent examinations were unremarkable and revealed no further explanation for the deterioration of the RLS symptoms. While the complexity of the patient's medical history had exposed her to a variety of medications, she reported that only lamotrigine, in addition to her original regimen of methadone and pramipexole, offered significant symptomatic relief. It must be noted that no adverse side effects, including impulse-control disorder, were reported by the patient. CONCLUSIONS: We present a case of a woman whose deteriorating symptoms of RLS were successfully alleviated by the administration of lamotrigine. This is only the third case in the literature to have successfully utilized lamotrigine as a treatment option for RLS.

Time-Course Changes in Lamotrigine Concentration after Addition of Valproate and the Safety and Long-Term Tolerability of Lamotrigine-Valproate Combination Therapy.

The aim of this study was to evaluate the time-course changes in lamotrigine (LTG) concentration after addition of valproate (VPA) and the safety and tolerability of the combination therapy. We reviewed our therapeutic drug monitoring (TDM) database and found 345 patients on LTG who received add-on therapy with VPA. VPA had been added at least 12 weeks after patients finished stepwise LTG titration. Also, we retrospectively evaluated the LTG concentration after addition of VPA and the safety and long-term tolerability of LTG-VPA combination therapy. Plasma LTG concentration increased more than 1.5-fold within 15 d of addition of VPA and reached a peak at 30 d. The rate of increase in LTG concentration occurred in a VPA concentration-dependent manner. During the first 120 d after addition of VPA, adverse events were reported by 58 patients (16.8%), but no patient developed cutaneous reactions. Kaplan-Meier analysis showed estimated retention rates for LTG-VPA combination therapy of 74.5% at 5 years. At 5 years, the mean concentration of LTG was 11.1 µg/mL (43.3 µmol/L). Because addition of VPA leads to a marked increase in LTG concentration over a short period, TDM for LTG should be performed at the earliest from 14 d after starting VPA. At 120 d after starting VPA therapy, the higher LTG concentration due to addition of VPA is not associated with an increased risk of cutaneous reactions. Although LTG-VPA combination therapy increases LTG concentration, it is well tolerated and has a high long-term retention rate.

Leukopenia associated with lamotrigine initiation after COVID-19 vaccine booster: A case report and literature review.

Adverse lamotrigine effects are more likely with concomitant use of antiepileptic drugs, rapid dose titration, and multiple drug use, highlighting the importance of measuring its concentration. Here, lamotrigine was administered the day after the third mRNA vaccination to a 20-year-old bipolar woman with these risk factors. Leukopenia occurred on day 12 without rapid concentration increase, but leukocytes gradually recovered after 22 weeks without discontinuation of lamotrigine. The second mRNA vaccination did not induce leukopenia. Possibly, a synergetic immune response to simultaneous vaccination and lamotrigine caused leukopenia, which recovered as the response weakened. Lamotrigine initiation immediately after mRNA vaccination may be a leukopenia risk factor.

Lamotrigine efficacy, safety, and tolerability for women of childbearing age with bipolar I disorder: Meta-analysis from four randomized, placebo-controlled maintenance studies.

This meta-analysis investigated the efficacy, safety, and tolerability of lamotrigine versus placebo in preventing relapse and recurrence of mood episodes in women of childbearing age with bipolar I disorder. Following up to 16 weeks' open-label lamotrigine treatment, responders were randomized to double-blind treatment, including lamotrigine 100-400 mg/day or placebo, in four trials of up to 76 weeks. Women aged 18-45 years who received ≥ 1 dose of study treatment and had ≥ 1 efficacy assessment in the double-blind phase were pooled for efficacy analysis. The primary outcome was median time to intervention for any mood episode (TIME). Of 717 eligible women in the open-label phase, 287 responded and were randomized to lamotrigine (n = 153) or placebo (n = 134). The randomized group had a mean (SD) of 2.0(2.02) manic and 2.5(2.02) depressive episodes in the 3 years before screening. Median TIME was 323 days with lamotrigine and 127 days with placebo (HR 0.69; 95% CI 0.49, 0.96; p = 0.030). Lamotrigine delayed time to intervention for any depressive episode (HR 0.59; 95% CI 0.39, 0.90; p = 0.014) with no treatment difference for manic episodes (HR 0.91; 95% CI 0.52, 1.58; p = 0.732). 2/717 (< 1%) participants experienced serious rash-related adverse events (AEs) during the open-label phase, and 52/717 (7%) had non-serious rash-related events leading to study withdrawal. Incidence of AEs and AEs leading to withdrawal were similar between lamotrigine and placebo groups. Lamotrigine delayed relapse and recurrence of mood episodes, largely by preventing depressive episodes, and was well tolerated in women of childbearing age.

Lamotrigine use and potential for adverse cardiac effects: A retrospective evaluation in a Veteran population.

OBJECTIVE: To identify the impact of lamotrigine (LTG) on cardiac rhythm and conduction abnormalities for Veterans, an especially vulnerable population. BACKGROUND: In October 2020 the US Food and Drug Administration (FDA) added a new warning to the label of lamotrigine (Lamictal™) regarding its potential to cause cardiac rhythm and conduction abnormalities [1]. This warning came following in vitro data which suggested Class IB antiarrhythmic effects occurring at clinically achievable concentrations of lamotrigine [2]. However, it is unclear whether the in vitro findings will result in adverse clinical outcomes. Our objective was to assess for evidence for adverse clinical outcomes in a vulnerable population and examine for subtler signs of an association between lamotrigine and cardiac rhythm disturbances. METHODS: A retrospective chart review was conducted using records between 10-01-2017 and 07-06-2021, identifying patients at the William S. Middleton Memorial Veterans Hospital who were prescribed lamotrigine. Data collected included: dates of lamotrigine initiation or discontinuation, lamotrigine dosing over the time of the prescription and maximum lamotrigine dose, any cardiac-related ICD-10-CM codes or a history of a cardiology appointment, EKGs with any abnormalities or changes, any concomitantly prescribed medications with known potential to cause cardiac abnormalities, any cardiac deaths. This retrospective chart review was approved by the University of Wisconsin-Madison Institutional Review Board. RESULTS: Two hundred and thirty-three (189 male) patients with a lamotrigine prescription and 41.2 % (n = 96) of these patients had an EKG performed while prescribed lamotrigine. The average age of patients was 64.3 ± 13.0 (range 29 to 90) years and mean maximum lamotrigine daily dose was 250.8 ± 148.2 mg (range 25 to 800 mg). Nearly half (47.9 %, 46/96) of the patients were prescribed a concomitant sodium channel blocking medication in addition to lamotrigine. Eighty-four of the patients (87.5 %, 84/96) had a cardiac diagnosis, while 12 (12.5 %, 12/96) did not. A total of 12 deaths occurred within the review period, with two cardiac deaths from congestive heart failure. Four cases did not have information on cause of death. No LTG-associated cardiac adverse effects were noted as part of clinical care, though rash was noted in 5 cases. A total of 7 (7.3 %, 7/96) patients were found to have EKG abnormalities potentially related to lamotrigine, including 7.1 % (6/84) of those with a cardiac diagnosis and 8.3 % (1/12) of those without a cardiac diagnosis. CONCLUSIONS: While recent FDA warnings have suggested caution regarding cardiac complications associated with lamotrigine based on in vitro studies, the clinical implications are uncertain. Despite selecting a particularly vulnerable population, this retrospective chart review did not identify any deaths due to cardiac rhythm or conduction causes, nor demonstrate unambiguous cardiac complications related to lamotrigine. Even using permissive criteria (including any prolonged PR or QTc) to examine for subtle effects, only a low incidence (<10 %) of potential complications was found. Broader implications of this study are limited by the number of patients included and the retrospective nature of the study. Therefore, further studies are warranted to evaluate a link between cardiac complications and the use of lamotrigine, including the role of concomitant medications such as other sodium channel blocking agents and psychotropic medications.

IDH2 mutations in acute myeloid leukemia.

Advances in the treatment of acute myeloid leukemia (AML) over the last 40 years have been limited. With an improved understanding of the pathophysiology of the disease, the advent of new treatment options has enriched the armamentarium of the physician to combat the disease. Mutations of the isocitrate dehydrogenase (IDHs) genes are common in AML and occur in 20-30% of cases. These mutations lead to DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation. Targeting mutant IDH, either as monotherapy or in combination with hypomethylating agents (HMAs) or BCL-2 inhibitors, has opened new avenues of therapy for these patients.This review will outline the function of IDHs and focus on the biological effects of IDH2 mutations in AML, their prognosis and treatment options.

Clinical and metabolomic characterization of Brivanib-Induced hypertension in metastatic colorectal cancer.

BACKGROUND: Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome. PATIENTS AND METHODS: Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R2 Y score = 0.89, Q2 Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found. CONCLUSION: TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.

A novel approach for pharmacological substantiation of safety signals using plasma concentrations of medication and administrative/healthcare databases: A case study using Danish registries for an FDA warning on lamotrigine.

PHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a warning on the antiseizure drug lamotrigine claiming that it has the potential to increase the risk of arrhythmias and related sudden cardiac death due to a pharmacological sodium channel-blocking effect. We hypothesized that the risk of arrhythmias and related death is due to toxicity. We used the PHARMACOM-EPI framework to investigate the relationship between lamotrigine's plasma concentrations and the risk of death in older patients using real-world data. Danish nationwide administrative and healthcare registers were used as data sources and individuals aged 65 years or older during the period 1996 - 2018 were included in the study. According to the PHARMACOM-EPI framework, plasma concentrations of lamotrigine were predicted at the time of death and patients were categorized into non-toxic and toxic groups based on the therapeutic range of lamotrigine (3-15 mg/L). Over 1 year of treatment, the incidence rate ratio (IRR) of all-cause mortality was calculated between the propensities score matched toxic and non-toxic groups. In total, 7286 individuals were diagnosed with epilepsy and were exposed to lamotrigine, 432 of which had at least one plasma concentration measurement The pharmacometric model by Chavez et al. was used to predict lamotrigine's plasma concentrations considering the lowest absolute percentage error among identified models (14.25 %, 95 % CI: 11.68-16.23). The majority of lamotrigine associated deaths were cardiovascular-related and occurred among individuals with plasma concentrations in the toxic range. The IRR of mortality between the toxic group and non-toxic group was 3.37 [95 % CI: 1.44-8.32] and the cumulative incidence of all-cause mortality exponentially increased in the toxic range. Application of our novel framework PHARMACOM-EPI provided strong evidence to support our hypothesis that the increased risk of all-cause and cardiovascular death was associated with a toxic plasma concentration level of lamotrigine among older lamotrigine users.

Lamotrigine in mood disorders: Flash survey on prescribing habits and blood tests practices.

OBJECTIVE: Therapeutic drug monitoring for lamotrigine is poorly documented in bipolar and depressive disorders. In order to evaluate its use among French psychiatrists, we explored prescribing habits, therapeutic monitoring and dosage adjustment of lamotrigine through a flash survey. METHODS: A survey was broadcasted by the network of Expert Centers for Bipolar Disorder and Resistant Depression and by the Collegial of Psychiatry of the Assistance publique des Hôpitaux de Paris. Questions concerned the frequency of prescribing depending on the mood disorder, the frequency of plasma levels, therapeutic monitoring, dosage adjustment and the limitation represented by dermatological risk. RESULTS: Of the 99 hospital psychiatrists who responded, 66 practiced in a university hospital and 62 for more than 5years. Overall, lamotrigine was more frequently prescribed for type 2 bipolar disorder (often: 51%) than for type 1 bipolar disorder (often: 22%). Dermatotoxicity was a major barrier to prescribing for 15% (n=13) of respondents. Nearly two-thirds of prescribers (61%, n=59) measured lamotrigine, of which 50% (n=29) systematically. However, 40% of them did not have an opinion on the optimal plasma concentration. In total, 22% (n=13) always adjusted the dosage according to the result. The first argument for dosage adjustment was clinical response for 80% (n=47) of prescribers, adverse effects for 17% (n=10) and plasma levels for only 4% (n=2). CONCLUSION: While many psychiatrists report using plasma dosage of lamotrigine, few use the plasma level result to adapt dosage and many have no opinion of the target values for plasma concentrations. This illustrates the lack of data and recommendations regarding the use of therapeutic pharmacological monitoring of lamotrigine in bipolar and depressive disorders.

Genetic predisposition for the development of lamotrigine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Studies report an association between the expression of HLA alleles and lamotrigine (LTG)-induced Stevens-Johnson syndrome (SJS). This systematic review and meta-analysis evaluates the association between HLA alleles and LTG-induced SJS in different populations. Two alleles, HLA-B*0702 and HLA-C*0702, were deemed to be protective; five alleles, HLA-B*1502, HLA-B*4403, HLA-A*2402, CYP2C19*2 and HLA-B*38, may play a role in LTG-induced SJS, for which only data studying HLA-B*1502 could be extracted. The pooled odds ratio of 2.88, 95% CI of 1.60-5.17 and p-value of 0.0004 establish the presence of HLA-B*1502 as a major risk factor for the development of LTG-induced SJS/toxic epidermal necrolysis (TEN). Although multiple alleles that may play a role in the development of LTG-induced SJS/TEN were identified, the expression of the risk alleles may be ancestry-specific, and genetic screening is warranted for preventing this life-threatening adverse drug reaction.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.