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Title: Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours.
Austin Authors: Nebot, Noelia;Arkenau, Hendrik-Tobias;Infante, Jeffrey R;Chandler, Jason C;Weickhardt, Andrew;Lickliter, Jason D;Sarantopoulos, John;Gordon, Michael S;Mak, Gabriel;St-Pierre, Annie;Tang, Lihua;Mookerjee, Bijoyesh;Carson, Stanley W;Hayes, Siobhan;Grossmann, Kenneth F
Affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA
Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, Victoria, Australia
Sarah Cannon Research Institute and University College London, London, W1G 6AD, UK
Nucleus Network, Melbourne, VIC, 3004, Australia
Sarah Cannon Research Institute, Nashville, TN, 37203, USA
West Cancer Center, Memphis, TN, USA
Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
Pinnacle Oncology Hematology/HonorHealth Research Institute, Scottsdale, AZ, 85258, USA
Sarah Cannon Research Institute UK, London, W1G 6AD, UK
Novartis Pharma AG, Basel, Switzerland
Novartis Pharmaceuticals Corporation, Morrisville, NC, USA
Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA
Novartis Pharmaceuticals Corporation, Morrisville, NC, USA
ICON, Marlow, UK
Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
Issue Date: Apr-2018
Date: 2018-01-23
Publication information: British Journal of Clinical Pharmacology 2018; 84(4): 764-775
Abstract: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. 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. 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 Cmax 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. Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen.
DOI: 10.1111/bcp.13488
ORCID: 0000-0001-8543-5844
Journal: British journal of clinical pharmacology
PubMed URL: 29243287
Type: Journal Article
Subjects: QT prolongation
drug safety
Appears in Collections:Journal articles

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