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

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

Br J Clin Pharmacol. 2012 Nov;74(5):788-96

Authors: Graham RA, Hop CE, Borin MT, Lum BL, Colburn D, Chang I, Shin YG, Malhi V, Low JA, Dresser MJ

Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: 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.
WHAT THIS STUDY ADDS: 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.
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 (14) C-vismodegib with single and multiple oral doses.
METHODS: 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?�g 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.
RESULTS: 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.
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.

PMID: 22458643 [PubMed - indexed for MEDLINE]

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