Search

Objective: Cenobamate (CNB), a recently approved antiseizure medication by the European Medicines Agency (EMA), serves as an adjunctive therapy for focal-onset seizures in adult patients unresponsive to at least two other treatments. Administered in polytherapy, CNB can potentially interact with co-administered drugs in epilepsy patients, necessitating dose adjustments and the need for effective therapeutic drug monitoring (TDM)., Methods: In this study, we introduce a novel LC-MS/MS method for precise CNB quantification using Volumetric Absorptive Microsampling (VAMS), following validation according to ICH guidelines M10. VAMS samples are efficiently extracted with 200 μL of methanol, with chromatographic separation achieved using an Acquity UPLC HSS PFP column. The method's efficacy was confirmed through its application to real samples from adult CNB-treated patients., Results: Our results demonstrate that the method exhibits linearity within the range of 0.05-30 mg/L, with intra- and inter-run precision ranging from 1% to 8% and accuracy from 1% to 10% based on 30 μL of sample. Furthermore, CNB stability in VAMS is confirmed for up to 15 days at 25°C and -20°C. Importantly, no significant difference was observed between CNB concentrations in VAMS samples and those in plasma obtained from venous blood., Significance: This VAMS-based LC-MS/MS method presents a robust alternative for TDM in CNB-treated patients. Future investigations should explore CNB concentrations in capillary blood and assess their correlation with plasma levels to further enhance its clinical utility., Plain Language Summary: Cenobamate is an antiepileptic drug and used for treatment of focal-onset seizures in adult patients (≥18 age). TDM can prevent drug interactions and minimize drug toxicity. The aim of this work is to evaluate volumetric absorptive microsampling (VAMS) from capillary blood as an alternative strategy for TDM in patients treated with the newly antiepileptic drug. Our method is suitable for TDM, and this study suggests that VAMS allows monitoring of cenobamate concentration and can offer valuable support for personalized therapy in refractory epilepsy., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Apixaban, a direct oral anticoagulant drug (DOAC), typically does not require routine therapeutic drug monitoring (TDM), yet recent guidelines propose its use in specific clinical scenarios. While various antifactor Xa (anti-FXa) chromogenic assays serve as useful proxies for measuring plasma exposure to apixaban in emergencies, they lack specificity compared with chromatographic methods. This research project is intended to the development and validation of a standardized protocol of liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conformity with the ICH guidelines M10 for the measurement of apixaban in both plasma and dried plasma spots (DPSs). Samples preparation included protein precipitation after the addition of a deuterated internal standard (IS), and the chromatographic separation was carried out on a Thermo Scientific™ Accucore™ Polar Premium column (50 mm × 2.1 mm, i.d. 2.6 m). The newly developed LC-MS/MS method for apixaban mesurement from both plasma and DPS resulted linear over a wide concentration range (31.25-500 ng/mL), accurate, and reproducible without matrix effects, allowing for specific and rapid quantification. Stability was assessed on quality controls and a real sample, allowing the setting up of a robust TDM protocol that was applied to five anonymized plasma samples obtained from adult patients undergoing apixaban treatment at steady-state. In conclusion our novel LC-MS/MS method is adequate for accurate apixaban quantitation from both plasma and DPS matrixes, and may thus facilitate the guidelines suggested implementation of apixaban TDM, even in peripheral hospitals through shipment of DPS at reference laboratories., (© 2024 The Author(s). Journal of Mass Spectrometry published by John Wiley & Sons Ltd.)

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and -20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Vancomycin is a glycopeptide antibiotic that has been adopted in clinical practice to treat gram-positive infections for more than 70 years. Despite vancomycin's long history of therapeutic use, optimal dose adjustments and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in children are still under debate. Therapeutic drug monitoring (TDM) has been widely integrated into pediatric clinical practice to maximize efficacy and safety of vancomycin treatment. Area under the curve (AUC)-guided TDM has been recently recommended instead of trough-only TDM to ensure PK/PD target attainment of AUC 0-24h /minimal inhibitory concentration (MIC) > 400 to 600 and minimize acute kidney injury risk. Bayesian forecasting in pediatric patients allows estimation of population PK to accurately predict individual vancomycin concentrations over time, and consequently total vancomycin exposure. AUC-guided TDM for vancomycin, preferably with Bayesian forecasting, is therefore suggested for all pediatric age groups and special pediatric populations. In this review we aim to analyze the current literature on the pediatric use of vancomycin and summarize the current knowledge on dosing optimization for target attainment in special patient populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging., Case Presentation: We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up., Conclusion: Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The prescriptive appropriateness of Proton Pump Inhibitors (PPIs) in polypharmacy is controversial. PPIs are often overprescribed and the risk of prescribing errors and adverse drug reactions increases for each additional drug added to therapy. Hence, guided deprescription should be considered and easily implementable in ward practice. This observational prospective study evaluated the implementation of a validated PPIs deprescription flow chart to real-life internal ward activity through the presence of a clinical pharmacologist as an enhancing additional factor by assessment of inhospital prescriber's adherence to the proposed flow chart. Patients' demographics and prescribing trends of PPIs prescriptions were analyzed by descriptive statistics. The final analysis of data included ninety-eight patients (forty-nine male and forty-nine female), aging 75.6 ± 10.6 years; 55.1% of patients had home-PPIs prescriptions, while 44.9% received inhospital-PPIs prescriptions. Evaluation of prescriber's adherence to the flow chart revealed that the percentage of patients with a prescriptive/deprescriptive pathway conforming to that of the flow chart was 70.4%, with low symptomatologic recurrences. The clinical pharmacologists' presence and influence in ward activity may have contributed to this finding, since continuous training of the prescribing physicians is deemed a success-related factor in the deprescribing strategy. Multidisciplinary management of PPIs deprescription protocols shows high adherence by prescribers in real-life hospital settings and low recurrence events.

The new breakthrough cystic fibrosis (CF) drug combination of ivacaftor (IVA), tezacaftor (TEZ), and elexacaftor (ELX), namely "caftor" drugs, directly modulates the activity and trafficking of the defective CF transmembrane conductance regulator protein (CFTR) underlying the CF disease. The role of therapeutic drug monitoring (TDM) of caftor drugs in clinical settings has recently been established. The availability of reliable and robust analytical methods for the quantification of IVA, TEZ, and ELX is essential to support dose-concentration-effect studies. We have developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the rapid and simultaneous quantification of IVA, TEZ, and ELX from the plasma of CF patients. The method was based on a rapid extraction protocol from 50 μL human plasma and separation on a reversed-phase C-18 HPLC column after the addition of deuterated internal standards. Accurate analyte quantification using multiple reaction monitoring (MRM) detection was then obtained using a Thermofisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. The method has been validated following international (EMA) guidelines for bioanalytical method validation and has been tested on plasma samples from 62 CF patients treated with the three-drug combination IVA/TEZ/ELX, marketed as Kaftrio ® or Trikafta ® , in steady-state condition. The assay was linear over wide concentration ranges (0.008-12 mg/L) in plasma for IVA, TEZ, and ELX, suitable for a broad range of plasma concentrations, and accurate and reproducible in the absence of matrix effects. The stability of analytes for at least 30 days at room temperature could allow for cost-effective shipment and storage. On the same day of sample collection, a sweat test was evaluated for 26 associated patients' samples, FEV1 (%) for 58, and BMI was calculated for 62. However, Spearman correlation showed no correlation between C through plasma concentrations of analytes (IVA, TEZ, ELX) and sweat test, FEV1 (%), or BMI. Our method proved to be suitable for TDM and could be helpful in assessing dose-concentration-response correlations in larger studies.

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients' quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM.

Personalization of busulfan (Bu) exposure via therapeutic drug monitoring (TDM) is recommended for patients treated with high-dose conditioning regimens. Several laboratories' developed methods are available in the literature with a lack of standardization. The aim of this study is to develop a new standardized LC-MS/MS method and validate it according to the international ICH M10 (EMA) guidelines. Our method is based on rapid protein precipitation from 50 µL plasma followed by separation on a reversed-phase C-18 UHPLC column after the addition of deuterated internal standard and has been tested on real samples from pediatric patients treated with myeloablative conditioning regimens, including Bu, before autologous or allogeneic hematopoietic stem cell transplantation (HSCT). The validated LC-MS/MS method is linear over wide concentration ranges (125-2000 ng/mL), accurate, and reproducible in the absence of matrix effects, allowing for the specific and rapid quantification of Bu and allowing next-dose recommendations to be made in a timely fashion to answer clinicians' needs. Given the lack of data on the stability of Bu in real clinical samples, stability was assessed both on quality controls and on real samples to set up a robust protocol in real-life conditions. This novel LC-MS/MS method is suitable for application to the TDM-guided personalization of conditioning treatments with high-dose busulfan in pediatric patients undergoing HSCT.

Inflammatory myopathies, including immune-mediated necrotizing myopathy (IMNM), are a rare and heterogeneous group of autoimmune diseases which can even involve extramuscular districts and seriously impact patients' quality of life. We report the case of a 76-year-old woman who developed muscle weakness, fatigue, and increased CK, following treatment with dapagliflozin, a sodium/glucose co-transporter 2 (SGLT2) inhibitor, and metformin. Neurophysiology, muscle biopsy, and antibody dosage confirmed the diagnosis of IMNM. The temporal correlation between the onset of clinical manifestations and the increase in the dosage of antidiabetic drugs, the improvement of symptoms with the dechallenge of dapagliflozin, and the exclusion of other possible causes triggering myopathy suggests that this may be the first case of dapagliflozin-induced myopathy, different from the former one associated with the use of SGLT2 inhibitors., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Iron-chelation therapy is life-saving in patients on a chronic transfusion regimen as it reduces organ damage related to iron deposition in the tissues. Deferasirox, an iron-chelator, is characterized by pharmacokinetics variability, and some patients may discontinue the treatment due to toxicities., Objective: Understanding whether deferasirox plasma levels are related to patients' specific characteristics could help to optimize DFX dosage., Methods: We analyzed deferasirox plasma concentration in 57 transfusion-dependent anemic patients using the HPLC method in this prospective-retrospective cohort study. All outpatients (3 to 98 years) were treated with deferasirox (film-coated tablet) for at least one year (median dose, 16.5 mg/Kg once a day). Deferasirox plasma concentration was normalized for dose/Kg (C/dose) and corrected with a linear regression model that relates C/dose and the time of blood sampling (C ref /dose)., Results: No significant differences in C ref /dose were found between males and females, either between different types of hemoglobinopathies or depending on the presence of the UGT1A1*28 polymorphism. C ref /dose has a positive and significant correlation with age, creatinine, and direct bilirubin. C ref /dose, instead, has a negative and significant correlation with Liver Iron Concentration (LIC), ferritin, and eGFR. C ref /dose was significantly different between three age categories <18yrs, 18-50yrs, and >50yrs, with C ref /dose median values of 1.0, 1.2, and 1.5, respectively., Conclusion: The study evidenced that to ensure the efficacy of deferasirox in terms of control over LIC and, at the same time, a lesser influence on renal function, the dose of the drug to be administered to an elderly patient could be reduced., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)