Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis

Fudio, S. ; Tabernero, J. ; Subbiah, V. ; Chawla, S.P. ; Moreno, V. ; Longo, F. ; Lopez, R. ; Anton, A. (Universidad de Zaragoza) ; Trigo, J.M. ; Shapiro, G. ; Jeong, W. ; Villalobos, V.M. ; Lubomirov, R. ; Fernandez-Teruel, C. ; Alfaro, V. ; Boni, V.

Resumen: 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 < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 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 ¿QTcF at each time point was < 20 ms. C-¿QTcF was explored using linear mixed-effects analysis. 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 ¿QTcF 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 ¿QTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. Conclusions: ECG parameters and C-¿QTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

Idioma: Inglés

DOI: 10.1007/s00280-020-04153-6

Año: 2021

Publicado en: CANCER CHEMOTHERAPY AND PHARMACOLOGY 87 (2021), 113–124
ISSN: 0344-5704

Factor impacto JCR: 3.288 (2021)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 160 / 279 = 0.573 (2021) - Q3 - T2
Categ. JCR: ONCOLOGY rank: 168 / 245 = 0.686 (2021) - Q3 - T3

Factor impacto CITESCORE: 5.9 - Medicine (Q1) - Pharmacology, Toxicology and Pharmaceutics (Q2) - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 0.848 - Cancer Research (Q1) - Toxicology (Q1) - Pharmacology (medical) (Q1) - Oncology (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)