Hoffman La Roche, 340 Kingsland Street, Nutley, NJ, 07110, USA,
Cancer Chemother Pharmacol. 2014 Jan;73(1):103-11. doi: 10.1007/s00280-013-2324-5. Epub 2013 Nov 1.
This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets).
Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2.
Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h.
Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.
本研究采用商业化制剂（240 毫克微粉化块状粉末薄膜包衣片剂），对 BRAF(V600E) 突变阳性转移性黑色素瘤患者进行每日两次（bid）服用 240-960 毫克维莫非尼的多次给药药代动力学特征研究。
黑色素瘤患者（N=52）被随机分配至四个维莫非尼剂量组（bid 服用 240、480、720 或 960 毫克，连续 14 天）。第 15 天早晨给药后，暂停给药直至第 22 天，此时患者重新开始服用维莫非尼。在第 1、9 和 15 天的早晨给药后采集系列药代动力学样本；在第 2 天采集谷浓度药代动力学样本。
维莫非尼浓度在第 15 天达到稳态，多次给药后增加；在测试的 4 倍剂量范围内，C(max)、AUC(0-8h)和 AUC(0-168h)增加了 3.3-3.8 倍。统计分析表明，在 240-960 mg bid 剂量范围内，剂量与比例呈正相关。在各个剂量组中，第 15 天的平均蓄积比（第 15 天的 AUC(0-8h)与第 1 天的 AUC(0-8h)比值）在 19-25 之间。在稳态时，维莫非尼的峰谷比在整个 bid 给药间隔表现出相对平坦的浓度时间曲线。在停药期间（第 15-22 天），维莫非尼的平均谷浓度降至最低水平；维莫非尼的平均终末半衰期为 31.5-38.4 h。
维莫非尼血浆浓度随每日两次 240 毫克bid 剂量的增加而累积。在 240-960 mg bid 剂量范围内，维莫非尼的暴露量（AUC 和 C(max)）与剂量呈比例，且在 bid 给药间隔内药物水平保持稳定。
