Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors.

Abstract

PURPOSE:

This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.

EXPERIMENTAL DESIGN:

Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS.

RESULTS:

The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.

CONCLUSIONS:

Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.

• Authors: Patricia M Lorusso, Antonio Jimeno, Grace Dy, Alex Adjei, Jordan Berlin, Lawrence Leichman, Jennifer A Low, Dawn Colburn, Ilsung Chang, Sravanthi Cheeti, Jin Y Jin, Richard A Graham
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 17 Pg. 5774-82 (Sep 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21753154 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Anilides
• Antineoplastic Agents
• Hedgehog Proteins
• HhAntag691
• Pyridines

Topics

• Anilides (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Hedgehog Proteins (antagonists & inhibitors)
• Humans
• Male
• Neoplasms (drug therapy, pathology)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)