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

SUMMARY

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-hour 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 hours postdose (2.86 milliseconds; 90% CI, −1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase > 60 milliseconds; QTcF > 500 milliseconds). 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 milliseconds (upper 90% CI, < 10 milliseconds). 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.

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