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Prospective simulations of human pharmacokinetic (PK) parameters and plasma concentration-time curves using in vitro in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) models are becoming a vital part of the drug discovery and development process. This paper presents a strategy to deliver prospective simulations in support of(More)
Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification(More)
Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug–drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib’s teratogenic potential warranted a DDI study with oral contraceptives (OCs). This single-arm, open-label(More)
A rapid equilibrium dialysis (RED) assay followed by a solid phase extraction (SPE) high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of unbound vismodegib in human plasma was developed and validated. The equilibrium dialysis was carried out using 0.3 mL plasma samples in the single-use plate(More)
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(More)
Vismodegib (GDC-0449) is is an orally available selective Hedgehog pathway inhibitor in development for cancer treatment. The drug is ≥95% protein bound in plasma at clinically relevant concentrations and has an approximately 200-fold longer single dose half-life in humans than rats. We have identified a strong linear relationship between plasma drug(More)
The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the(More)
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