Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours
| Autor: | Theresa L. Werner, John W. Bauman, YanYan Zhou, Bela Rajiv Patel, Sunil Sharma, Kyriakos P. Papadopoulos, Amita Patnaik, Donna S. Cox, Mohammed Hamid, Drew W. Rasco, Anthony W. Tolcher, Daniel Schramek, Murali Beeram, Anita Scheuber |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Adolescent Pyridones MAP Kinase Kinase 2 MAP Kinase Kinase 1 Antineoplastic Agents Pyrimidinones 030204 cardiovascular system & hematology Toxicology QT interval Models Biological 03 medical and health sciences Electrocardiography Young Adult 0302 clinical medicine Internal medicine Neoplasms medicine Humans Pharmacology (medical) Single-Blind Method 030212 general & internal medicine Adverse effect Protein Kinase Inhibitors Aged Pharmacology Trametinib Cardiotoxicity medicine.diagnostic_test business.industry MEK inhibitor Cardiac arrhythmia Middle Aged medicine.disease Oncology Heart failure Area Under Curve Cardiology Electrocardiography Ambulatory Female business |
| Zdroj: | Cancer chemotherapy and pharmacology. 78(3) |
| ISSN: | 1432-0843 |
| Popis: | Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated.Eligible patients with solid tumours received placebo on day 1, once-daily trametinib 2-mg doses on days 2-14, and a single trametinib 3-mg dose on day 15 to achieve supratherapeutic dosing for QTc measurement. Electrocardiogram was assessed by 12-lead ambulatory 24-h Holter monitoring pre-dose, and on day 1 and day 15. Pharmacokinetic (PK) and pharmacodynamics (PD) parameters were measured.Thirty-two of 35 patients completed the study. There was no effect of trametinib when compared with time-matched placebo on the change from baseline in QTcF, QTcB, or QTcI interval. Mean AUC0-24 and C max following trametinib 2-mg repeat doses were 364 ng.h/mL and 22.9 ng/mL, respectively; the corresponding values for the 3-mg dose were 454 ng.h/mL and 29.2 ng/mL. Median T max was approximately 2 h for both doses. Statistical analysis and PK/PD modelling showed no significant relationship between QTcF interval and trametinib plasma concentrations. AEs were consistent with those reported previously. No electrocardiogram abnormalities were reported as AEs.The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure. |
| Databáze: | OpenAIRE |
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