An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

B C Goh; N J Reddy; U B Dandamudi; K H Laubscher; T Peckham; J P Hodge; A B Suttle; T Arumugham; Y Xu; C-F Xu; J Lager; M M Dar; L D Lewis

doi:10.1038/clpt.2010.158

An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

Clin Pharmacol Ther. 2010 Nov;88(5):652-9. doi: 10.1038/clpt.2010.158. Epub 2010 Sep 29.

Authors

B C Goh¹, N J Reddy, U B Dandamudi, K H Laubscher, T Peckham, J P Hodge, A B Suttle, T Arumugham, Y Xu, C-F Xu, J Lager, M M Dar, L D Lewis

Affiliation

¹ Section of Clinical Pharmacology, Department of Hematology-Oncology, National University Hospital, Singapore, Singapore.

PMID: 20881954
DOI: 10.1038/clpt.2010.158

Abstract

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.

Trial registration: ClinicalTrials.gov NCT00401583.

Publication types

Clinical Trial
Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Aged
Angiogenesis Inhibitors / administration & dosage*
Angiogenesis Inhibitors / adverse effects
Angiogenesis Inhibitors / pharmacokinetics
Cytochrome P-450 Enzyme Inhibitors*
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism
Drug Interactions
Female
Genotype
Humans
Indazoles
Isoenzymes
Male
Middle Aged
Molecular Probes
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / pathology
New Hampshire
Phenotype
Polymorphism, Genetic
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / pharmacokinetics
Pyrimidines / administration & dosage*
Pyrimidines / adverse effects
Pyrimidines / pharmacokinetics
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
Receptors, Vascular Endothelial Growth Factor / metabolism
Singapore
Substrate Specificity
Sulfonamides / administration & dosage*
Sulfonamides / adverse effects
Sulfonamides / pharmacokinetics
Treatment Outcome

Substances

Angiogenesis Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Indazoles
Isoenzymes
Molecular Probes
Protein Kinase Inhibitors
Pyrimidines
Sulfonamides
pazopanib
Cytochrome P-450 Enzyme System
Receptors, Vascular Endothelial Growth Factor

Associated data

ClinicalTrials.gov/NCT00401583