@article{7f467eedddba47bbbcb6fd34edf51938,
title = "Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600–mutant tumours",
abstract = " Aims: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600–mutant tumours. Methods: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib-matched placebo on day −1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. Results: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum ΔΔQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, −1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg C max and AUC (0–∞) were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC (0-τ) with 300 mg BID was ≈ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. Conclusion: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen. ",
keywords = "QT prolongation, drug safety, oncology, pharmacodynamics, pharmacokinetics",
author = "Noelia Nebot and Arkenau, {Hendrik Tobias} and Infante, {Jeffrey R.} and Chandler, {Jason C.} and Andrew Weickhardt and Lickliter, {Jason D.} and John Sarantopoulos and Gordon, {Michael S.} and Gabriel Mak and Annie St-Pierre and Lihua Tang and Bijoyesh Mookerjee and Carson, {Stanley W.} and Siobhan Hayes and Grossmann, {Kenneth F.}",
note = "Funding Information: We thank the patients who participated in this study and all the personnel involved in patient care and data collection. This study was sponsored by GlaxoSmithKline; however, as of 2 March 2015, dabrafenib became an asset of Novartis AG. This study is registered on the US National Institutes of Health website ClinicalTrials.gov (NCT01738451). Additionally, medical writing assistance, in the form of collating author comments and copyediting, and editorial assistance was provided by Amanda L. Kauffman, PhD (ArticulateScience LLC), and funded by Novartis Pharmaceuticals Corporation. The authors also wish to acknowledge Catrin Dalton and Christopher Jefferds of ICON for operational aspects of the study, Guenter Heimann of Novartis for assistance with reviewing PK/PD analyses included in this study. The authors received study funding from Cancer Center Support Grant P30 CA054174 (Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX). Funding Information: N.N., A.S. and B.M. are employees of Novartis. S.W.C. was an employee of GlaxoSmithKline and was an employee of Novartis. L.T. was an employee of Novartis. J.R.I. was a consultant for BioMed Valley, ARIAD Biosciences and Novartis. J.C.C. was a consultant for Bristol-Myers Squibb and served on the speakers bureau for Janssen. M.S.G. received research funding from Genentech Roche and GlaxoSmithKline. B.M. has stock ownership in Novartis, GlaxoSmithKline, Incyte and AstraZeneca. S.W.C. had equity ownership of GlaxoSmithKline and Novartis. S.H. was a consultant for ICON. H.T.A., A.W., J.D.L, J.S., G.M. and K.F.G. have no relationships to disclose. Publisher Copyright: {\textcopyright} 2017 The British Pharmacological Society",
year = "2018",
month = apr,
doi = "10.1111/bcp.13488",
language = "English (US)",
volume = "84",
pages = "764--775",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "4",
}