Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

摘要

AIM 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 14C-vismodegib with single and multiple oral doses. METHODS Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150mg vismodegib oral dose with a 14C-labelled 10μg i.v. bolus dose administered 2h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for 14C-vismodegib by accelerator mass spectrometry. RESULTS Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4mlh -1, 16.4l 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 78.5mlh -1 and 26.8l, 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. CONCLUSION 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.