A clinical drug–drug interaction study to evaluate the effect of a proton-pump inhibitor, a combined P-glycoprotein/cytochrome 450 enzyme (CYP)3A4 inhibitor, and a CYP2C9 inhibitor on the pharmacokinetics of vismodegib

• Published in: Cancer chemotherapy and pharmacology Vol. 78; no. 1; pp. 41 - 49
• Main Authors: Malhi, Vikram, Colburn, Dawn, Williams, Sarah J., Hop, Cornelis E. C. A., Dresser, Mark J., Chandra, Priya, Graham, Richard A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2016; Springer Nature B.V
• Subjects: Anilides - administration & dosage; Anilides - pharmacokinetics; Area Under Curve; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cancer Research; confidence interval; cytochrome P-450; Cytochrome P-450 CYP2C9 Inhibitors - administration & dosage; Cytochrome P-450 CYP2C9 Inhibitors - pharmacology; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Interactions; enzymes; Erinaceidae; Female; fluconazole; Fluconazole - administration & dosage; Fluconazole - pharmacology; Humans; Hydrogen-Ion Concentration; itraconazole; Itraconazole - administration & dosage; Itraconazole - pharmacology; Medicine; Medicine & Public Health; Oncology; Original; Original Article; P-glycoproteins; pharmacokinetics; Pharmacology/Toxicology; proton pump; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - pharmacology; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Rabeprazole - administration & dosage; Rabeprazole - pharmacology; risk; Solubility; Clinical pharmacology; CYP inhibitors; Clinical drug–drug interaction; Pharmacokinetic; Proton-pump inhibitor; P-glycoprotein inhibitor
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-016-3020-z

Purpose 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 P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. Methods Cohorts included a control arm ( n  = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n  = 24); itraconazole 200 mg ( n  = 22); or fluconazole 400 mg ( n  = 22). Results Area under the vismodegib concentration–time curve from zero to 24 h (AUC 0–24h ) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC 0–24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. Conclusion The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug–drug interaction. ClinicalTrials.gov Identifier NCT01772290.