Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis

摘要: In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including gastrointestinal stromal tumor (GIST) metastatic renal cell carcinoma (mRCC). Pharmacodynamic data were available for 639 of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models express endpoint values and/or changes baseline by the highest-correlating measures developed S-PLUS NONMEM using fixed- mixed-effects modeling. Tentative identified (1) steady-state AUC total drug (sunitinib + its active metabolite SU12662) time progression (TTP), overall survival (OS), significantly associated longer TTP OS GIST mRCC, incidence, but not severity, fatigue; (2) response probability, objective mRCC stable disease both (with no such correlations tumors); (3) dose size reductions; (4) concentration diastolic blood pressure (DBP), a typical patient on 50 mg (the recommended dose) predicted experience maximum DBP increase 8 mmHg; (5) cumulative absolute neutrophil count (ANC), ANC reductions occurring predominantly after one treatment cycle. The results meta-analysis indicate that increased is improved outcomes (longer TTP, OS, greater chance antitumor response), as well some risk adverse effects. A 50-mg starting seems reasonable, providing benefit acceptably low events.