Impact of pazopanib on docetaxel exposure: results of a phase I combination study with two different docetaxel schedules

Purpose There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib w...

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Published in:	Cancer chemotherapy and pharmacology Vol. 75; no. 2; pp. 365 - 371
Main Authors:	Hamberg, P., Mathijssen, R. H. J., de Bruijn, P., Leonowens, C., van der Biessen, D., Eskens, F. A. L. M., Sleijfer, S., Verweij, J., de Jonge, M. J. A.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2015 Springer Nature B.V
Subjects:	Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents, Phytogenic - administration & dosage Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cancer Research Drug Interactions Female Humans Male Maximum Tolerated Dose Medicine Medicine & Public Health Middle Aged Neoplasms - drug therapy Oncology Original Article Pharmacology/Toxicology Pyrimidines - administration & dosage Sulfonamides - administration & dosage Taxoids - administration & dosage Phase I Pharmacokinetics CYP3A4 OATP1B Pazopanib Docetaxel
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Summary:	Purpose There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. Methods In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. Results Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m 2 , while for D1w MTD, it was 20 mg/m 2 . In the D3w schedule, the administration of pazopanib led to a 33 % lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m 2 ; P = 0.019) and >50 % increase in AUC 0-∞ (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. Conclusions Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-014-2655-x