Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis
| Autor: | Woondong Jeong, Federico Longo, Rafael López, Jose Manuel Trigo, Antonio Antón, Victor Moreno, Valentina Boni, Carlos Fernández-Teruel, Rubin Lubomirov, Geoffrey I. Shapiro, Salvador Fudio, Josep Tabernero, Vivek Subbiah, Victor M. Villalobos, Vicente Alfaro, Sant P. Chawla |
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| Přispěvatelé: | Institut Català de la Salut, [Fudio S] PharmaMar, 28770 Madrid, Spain. [Tabernero J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Subbiah V] The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. [Chawla SP] Sarcoma Oncology Center, Santa Monica, CA 90403, USA. [Moreno V] Fundación Jiménez Díaz, 28040 Madrid, Spain. [Longo F] Hospital Ramon y Cajal, 28034 Madrid, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
Lurbinectedin
Male Cancer Research Toxicology Other subheadings::Other subheadings::/drug therapy [Other subheadings] Medicaments antineoplàstics Electrocardiography Neoplasms QTcF Pharmacology (medical) Prospective Studies Prospective cohort study Plasma concentration Effect compartment medicine.diagnostic_test Càncer - Tractament Middle Aged Oncology Cardiology Other subheadings::Other subheadings::/administration & dosage [Other subheadings] Original Article Female Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] Adult medicine.medical_specialty Cmax Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Antineoplastic Agents QT interval Heterocyclic Compounds 4 or More Rings neoplasias [ENFERMEDADES] Internal medicine medicine Medicaments - Efectes fisiològics Humans In patient Time point Aged Pharmacology Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores] Cardiac repolarization business.industry ECG acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] Confidence interval Neoplasms [DISEASES] business Carbolines |
| Zdroj: | Zaguán. Repositorio Digital de la Universidad de Zaragoza instname Cancer Chemotherapy and Pharmacology Zaguán: Repositorio Digital de la Universidad de Zaragoza Universidad de Zaragoza Scientia |
| Popis: | Purpose This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors. Methods Patients with QTcF ≤ 500 ms, QRS 2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was Results A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. Conclusions ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization. |
| Databáze: | OpenAIRE |
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