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

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. 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 14 C-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 14 C-labelled 10 mg 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. 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.

U.S. Food and Drug Administration Approval: Vismodegib for Recurrent, Locally Advanced, or Metastatic Basal Cell Carcinoma

“…The absolute bioavailability of vismodegib after a single 150 mg oral dose was 31.8% with saturable absorption as evidenced by the lack of dose-proportional increases in exposure after single doses of 270 mg or 540 mg compared with 150 mg (18). Food intake did not affect vismodegib exposure at steady state.…”

Vismodegib for the treatment of basal cell skin cancer

“…dose (13 days). 10 After a single dose, vismodegib had a moderate volume of distribution (V) of 16.4 L and an absolute bioavailability of 31.8%.…”

“…10 Subjects received a 10-mg 14 C-labeled i.v. bolus dose of vismodegib administered two hours after administration of a single 150-mg oral dose of vismodegib (6 patients) or after seven days of using vismodegib 150 mg daily orally (6 patients).…”

Vismodegib Provides a Novel Treatment for Advanced Basal Cell Carcinoma

“…Elimination of vismodegib is primarily through the liver, with 82% of the drug recovered in the feces and 4.4% found in the urine [11]. The elimination half-life is about 12 days after a single dose, but decreases to 4 days with daily continuous dosing [3,5,12]. …”