Novartis Pharmaceuticals Corporation, East Hanover, NJ, 07936, USA.
Sarah Cannon Research Institute and University College London, London, W1G 6AD, UK.
Br J Clin Pharmacol. 2018 Apr;84(4):764-775. doi: 10.1111/bcp.13488. Epub 2018 Jan 23.
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 C and AUC were ≈ 2-fold higher than with single-dose 150 mg. Day 8 AUC 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.
评估 BRAF 抑制剂达拉非尼重复口服超治疗剂量对 BRAF V600 突变肿瘤患者 QTc 间期的影响。
这项 1 期、多中心、2 部分研究（BRF113773/NCT01738451）的第 1 部分评估了达拉非尼 225 或 300mg 每日 2 次（BID）给药的安全性/耐受性，为第 2 部分剂量提供依据。第 2 部分患者在第-1 天接受达拉非尼匹配安慰剂，第 1 天单次给予达拉非尼 300mg，第 2 天至第 7 天给予 300mg BID，第 8 天（上午）给予 300mg，随后在每个剂量日进行 24 小时动态心电图监测和药代动力学样本采集。药代动力学/药效学分析评估了达拉非尼和代谢物联合对 QTc 间期的影响。
第 1 部分（n=12）确定了 300mg BID 的超治疗剂量用于第 2 部分。31 名患者完成了第 2 部分。最大平均ΔΔQTcF 发生在第 8 天，给药后 10 小时（2.86msec；90%CI，-1.36 至 7.07）。分类分析显示无安慰剂和达拉非尼离群值（增加>60msec；QTcF>500msec）。第 1 天 300mg 达拉非尼 C 和 AUC 约为单次给予 150mg 的 2 倍。第 8 天 300mg BID 的 AUC 约为 150mg BID 的 2.7 倍。达拉非尼代谢物显示出相似的趋势。药代动力学/药效学建模/模拟显示，中位数 QTc 增加<5msec（90%CI 上限<10msec）。超治疗剂量给药未出现意外毒性。
重复口服超治疗剂量的达拉非尼 300mg BID 给药对 QTc 间期无临床相关影响，未见新的安全性信号。
