DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol / Genotipado del gen DPYD y toxicidad de 5-fluoropirimidinas: Protocolo de una revisión de revisiones sistemáticas

Introduction: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase (DPD) deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in DPD deficient patients. The main objective of this overview of systematic reviews is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity.Methods and analysis: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus, and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment, and data collection. Discrepancies will be solved by a third investigator.(AU)

Introducción: El incremento del riesgo de toxicidad grave y potencialmente mortal en pacientes con deficiencia de dihidropiridina deshidrogenasa (DPD) en tratamiento con fluoropirimidinas ha sido ampliamente estudiado. Una revisión actualizada de las revisiones sistemáticas publicadas, que agrupe la literatura existente, puede añadir valor al resaltar la información más relevante y respaldar la toma de decisiones con respecto al tratamiento en pacientes con deficiencia de DPD. El objetivo principal de esta revisión de revisiones sistemáticas es identificar revisiones sistemáticas publicadas sobre la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. Métodos y análisis: Este protocolo se ha desarrollado siguiendo la lista de verificación de los Protocolos para Revisiones Sistemáticas y Metaanálisis Preferidos (PRISMA-P), y la revisión de las revisiones sistemáticas se comunicará de acuerdo con la declaración PRISMA. Se realizará una búsqueda en PubMed, Embase, Scopus y la Biblioteca Cochrane desde su inicio hasta 2023. Se considerarán aquellas revisiones sistemáticas, independientemente de los diseños de estudio, que analicen la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. La calidad metodológica se evaluará utilizando la lista de verificación AMSTAR2 (Herramienta de Medición para Evaluar Revisiones Sistemáticas 2). Dos investigadores independientes realizarán la selección de estudios, la evaluación de la calidad y la recopilación de datos. Las discrepancias se resolverán mediante un tercer investigador.(AU)

Genotipado del gen DPYD y toxicidad de 5-fluoropirimidinas: Protocolo de una revisión de revisiones sistemáticas / DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol

Introduction: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase (DPD) deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in DPD deficient patients. The main objective of this overview of systematic reviews is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity.Methods and analysis: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus, and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment, and data collection. Discrepancies will be solved by a third investigator.(AU)

Introducción: El incremento del riesgo de toxicidad grave y potencialmente mortal en pacientes con deficiencia de dihidropiridina deshidrogenasa (DPD) en tratamiento con fluoropirimidinas ha sido ampliamente estudiado. Una revisión actualizada de las revisiones sistemáticas publicadas, que agrupe la literatura existente, puede añadir valor al resaltar la información más relevante y respaldar la toma de decisiones con respecto al tratamiento en pacientes con deficiencia de DPD. El objetivo principal de esta revisión de revisiones sistemáticas es identificar revisiones sistemáticas publicadas sobre la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. Métodos y análisis: Este protocolo se ha desarrollado siguiendo la lista de verificación de los Protocolos para Revisiones Sistemáticas y Metaanálisis Preferidos (PRISMA-P), y la revisión de las revisiones sistemáticas se comunicará de acuerdo con la declaración PRISMA. Se realizará una búsqueda en PubMed, Embase, Scopus y la Biblioteca Cochrane desde su inicio hasta 2023. Se considerarán aquellas revisiones sistemáticas, independientemente de los diseños de estudio, que analicen la asociación entre variaciones en el linaje germinal del gen DPYD y la toxicidad de las fluoropirimidinas. La calidad metodológica se evaluará utilizando la lista de verificación AMSTAR2 (Herramienta de Medición para Evaluar Revisiones Sistemáticas 2). Dos investigadores independientes realizarán la selección de estudios, la evaluación de la calidad y la recopilación de datos. Las discrepancias se resolverán mediante un tercer investigador.(AU)

DPYD genotyping and 5-fluoropyrimidine toxicity: An overview of systematic reviews protocol. / [Artículo traducido] Genotipado del gen DPYD y toxicidad de las 5-fluoropirimidinas: protocolo de un resumen de revisiones sistemáticas.

INTRODUCTION: The increased risk of severe and life-threatening toxicity in patients with dihydropyridine dehydrogenase deficiency, under treatment with fluoropyrimidines, has been widely studied. An up-to-date overview of systematic reviews summarizing existing literature can add value by highlighting most relevant information and supports decision-making regarding treatment in dihydropyridine dehydrogenase deficient patients. The main objective of this overview is to identify published systematic reviews on the association between germline variations in the DPYD gene and fluoropyrimidine toxicity. METHODS AND ANALYSIS: This protocol was developed following the Preferred Reported Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) checklist, and the overview of systematic reviews will be reported in accordance with the PRISMA statement. PubMed, Embase, Scopus and the Cochrane Library will be searched from inception to 2023. Systematic reviews irrespective of study designs that analyze the association between germline variations in the DPYD and fluoropyrimidine toxicity will be considered. Methodological quality will be assessed using AMSTAR2 checklist (Measurement Tool to Assess Systematic Reviews 2). Two independent investigators will perform the study selection, quality assessment and data collection. Discrepancies will be solved by a third investigator.

First reported double drug-drug interaction in a cancer renal patient under everolimus treatment: therapeutic drug monitoring and review of literature.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities.

Therapeutic Drug Monitoring of Lacosamide: Is 10 to 20 mg/L a Suitable Reference Range for Patients With Epilepsy?

OBJECTIVES: The reference range for lacosamide (LCM) has been updated from 1 to 10 mg/L to 10 to 20 mg/L. Historically, LCM range was defined from trough-level measurements, but the newer ranges were obtained from peak-level measurements. The purpose of the study was to evaluate the relationship between LCM plasma levels higher than 10 mg/L and the incidence of adverse effects. METHODS: This was a single-center, retrospective, observational study of adult outpatients with epilepsy who were prescribed LCM and had LCM serum concentrations (LCM-SCs) >10 mg/L on drug-fasting samples, measured from June 2017 to December 2020. RESULTS: A total of 55 LCM-SC samples corresponding to 44 patients (25 women [57%]) were analyzed. The median age was 47 (39-61) years. The median LCM-SC was 13.4 (11.2-17.8) mg/L. Adverse effects were reported in 18 patients (41%). Forty-eight percent (21 of 44) of patients required an LCM dose reduction, with a mean LCM-SC of 16.0 (13.2-18.1) mg/L, whereas, in the remaining patients (23 of 44), LCM dose was not modified, with a mean LCM-SC of 12.2 (10.7-14.2) mg/L ( P = 0.0244). Forty-one percent (18 of 44) of patients reported adverse effects related to LCM, with a mean LCM-SC of 15.6 (12.7-18.4) mg/L, whereas, in the remaining patients (26 of 44), adverse effects did not occur, with a mean LCM-SC of 12.6 (10.7-16.5) mg/L ( P = 0.0495). CONCLUSIONS: The 10 to 20 mg/L reference range clearly increases toxicity in patients treated with LCM. Adjusting the reference range upper limit to 12 mg/L with a routine therapeutic drug monitoring program is suggested, to achieve a reasonable probability of efficacy and decrease toxicity.