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Open Access 01-07-2016 | Original Article

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

Authors: Vikram Malhi, Dawn Colburn, Sarah J. Williams, Cornelis E. C. A. Hop, Mark J. Dresser, Priya Chandra, Richard A. Graham

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2016

Abstract

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.

Available only for authorised users

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Title: 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
Authors: Vikram Malhi
Dawn Colburn
Sarah J. Williams
Cornelis E. C. A. Hop
Mark J. Dresser
Priya Chandra
Richard A. Graham
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3020-z

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Abstract

Purpose

Methods

Results

Conclusion

ClinicalTrials.gov Identifier

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