title: Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA. Amita.Patnaik@start.stoh.com.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Beeram
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Rasco
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Werner
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, 27709, USA.|Quinitles, 4820 Emperor Boulevard, Durham, NC, 27703, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Bauman
authors.affiliation: MedImmune, 1 Medimmune Way, Gaithersburg, MD, 20878, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Scheuber
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA.|Teva Pharmaceuticals Industries, Ltd., 1090 Horsham Road, North Wales, PA, 19454, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA, USA.
authors.forename: Bela R
authors.initials: BR
authors.lastname: Patel
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA.
authors.forename: YanYan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Hamid
authors.affiliation: GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.affiliation: Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D066126:Cardiotoxicity / Q000453:epidemiology; D004562:Electrocardiography; D015716:Electrocardiography, Ambulatory; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: Cancer; Cardiac repolarization; MEK inhibitor; QT interval; Trametinib