Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Br J Clin Pharmacol. 2012 Nov;74(5):788-96. doi: 10.1111/j.1365-2125.2012.04281.x.
While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity.
This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing.
Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses.
Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry.
Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.
Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.
最近的出版物表明，维莫德吉的药代动力学（PK）似乎呈非线性，但尚未有报告描述非线性的机制。
本研究提供了证据表明，两种不同的过程，即溶解度限制的吸收和浓度依赖性血浆蛋白结合，可解释维莫德吉的非线性 PK。本研究提供了定量结果，可以解释连续每日给药时维莫德吉预期积累量较低的原因。
维莫德吉已在晚期基底细胞癌患者中显示出临床活性。维莫德吉的药代动力学（PK）呈非线性。本研究的目的是通过单次和多次口服剂量后给予（14）C-维莫德吉示踪静脉（i.v.）剂量，确定重复给药后维莫德吉 PK 是否发生变化。
健康绝经后女性受试者（n=6/组）接受单次或每日 150 mg 维莫德吉口服剂量，单次或最后一次口服剂量后 2 小时给予（14）C 标记的 10 µg i.v. 推注剂量（第 7 天）。通过 LC-MS/MS 测定维莫德吉的血浆样品，并通过加速器质谱法测定（14）C-维莫德吉。
单次静脉注射后，平均清除率、分布容积和绝对生物利用度分别为 43.4 ml/h（-1）、16.4 l 和 31.8%。单次口服和 i.v. 给予维莫德吉后平行的浓度-时间曲线表明消除率有限的 PK。稳态时静脉注射后，平均清除率和分布容积分别为 78.5 ml/h（-1）和 26.8 l。单次和多次口服给药后 i.v. PK 参数的比较表明，半衰期相似，清除率和分布容积增加（分别增加 81%和 63%），生物利用度降低（降低 77%）。与单次剂量相比，连续每日给药时维莫德吉的未结合分数增加了 2.4 倍。
口服和静脉给予维莫德吉后，维莫德吉的半衰期较长，绝对生物利用度中等，重复给药后 PK 呈非线性。本研究结果表明，维莫德吉的非线性 PK 是由两个独立的、非线性过程引起的，即溶解度限制的吸收和高亲和力、饱和的血浆蛋白结合。
