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

• 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
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2655-x

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.