Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects |
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Authors: | Graham Richard A Hop Cornelis E C A Borin Marie T Lum Bert L Colburn Dawn Chang Ilsung Shin Young G Malhi Vikram Low Jennifer A Dresser Mark J |
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Institution: | Genentech Inc., South San Francisco, CA, USA. |
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Abstract: | AIMVismodegib 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.METHODSHealthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a 14C-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 14C-vismodegib by accelerator mass spectrometry.RESULTSFollowing 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.CONCLUSIONVismodegib 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. |
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Keywords: | absolute bioavailability clearance GDC-0449 of distribution vismodegib volume |
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