F. Hoffmann-La Roche Ltd., New York, New York, USA.
pRED Roche Innovation Centre Welwyn, Roche Products Ltd., Welwyn Garden City, UK.
Clin Pharmacol Drug Dev. 2020 Jul;9(5):651-658. doi: 10.1002/cpdd.788. Epub 2020 Apr 20.
This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAF mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (C ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for C , AUC , and AUC of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.
这项 1 期开放标签、多中心、3 期、固定序列研究评估了多次给予维莫非尼对 1 例BRAF 突变阳性转移性恶性肿瘤患者给予单剂量替扎尼定（CYP1A2 探针底物）的药代动力学的影响。患者在第 1 天（A 期）接受单剂量替扎尼定 2mg，在第 2-21 天（B 期）每天接受维莫非尼 960mg 两次，在第 22 天（C 期）接受单剂量替扎尼定 2mg 和维莫非尼 960mg 两次。使用方差分析模型比较了 16 例患者在 A 期（替扎尼定单药）和 C 期（替扎尼定加维莫非尼）中替扎尼定的 AUC 和 C 的对数转换面积（AUC）和最大血浆浓度（C ）值。多次给予维莫非尼增加了 1 剂量替扎尼定的血浆暴露，C 、AUC 和 AUC 的几何均数比值（C 期/ A 期）分别为 2.15（90%CI，1.71-2.71）、4.22（90%CI，3.37-5.28）和 4.74（90%CI，3.55-6.33）；90%CI 均超出了无药物相互作用的预设范围（0.82-1.22）。本研究证实维莫非尼在体内为 CYP1A2 的中度抑制剂，与替扎尼定存在统计学显著的药物相互作用。当与 CYP1A2 底物同时给药时应谨慎使用维莫非尼。
