Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600–mutant tumours

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 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