Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis
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In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC).
Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models to express endpoint values and/or changes from baseline by the highest-correlating exposure measures were developed in S-PLUS or NONMEM using fixed- and mixed-effects modeling.
Tentative relationships were identified between (1) steady-state AUC of total drug (sunitinib + its active metabolite SU12662) and time to tumor progression (TTP), overall survival (OS), with AUC significantly associated with longer TTP and OS in patients with GIST and mRCC, and incidence, but not severity, of fatigue; (2) steady-state AUC of sunitinib and response probability, with AUC significantly associated with objective response in patients with mRCC and stable disease in patients with both mRCC and GIST (with no such correlations in patients with solid tumors); (3) dose and tumor size reductions; (4) total drug concentration and diastolic blood pressure (DBP), with a typical patient on sunitinib 50 mg QD (the recommended dose) predicted to experience a maximum DBP increase of 8 mmHg; and (5) cumulative AUC of total drug and absolute neutrophil count (ANC), with ANC reductions occurring predominantly after one treatment cycle.
The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.
KeywordsSunitinib Pharmacodynamic Pharmacokinetic Correlation Exposure Endpoints
The authors thank all of the patients and their families for their participation in the studies described herein. This work was supported in part by funding from Pfizer Inc, as well as support from the Ludwig Trust for Cancer Research (to G. D. Demetri). Editorial assistance was provided by ACUMED® (Tytherington, UK) and funded by Pfizer Inc.
Conflict of interest statement
B.E. Houk and C.L. Bello are full-time employees of Pfizer with stock ownership. B. Poland has a consultant/advisory role with Pharsight Corporation. L.S. Rosen has had a consultant/advisory role with and received funding from Pfizer. G.D. Demetri has had a consultant/advisory role with and received remuneration and funding from Novartis and Pfizer. R.J. Motzer has had a consultant/advisory role with Novartis and GlaxoSmithKline and received funding from Pfizer, Wyeth, and GlaxoSmithKline.
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