title: Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pfizer Inc., Global Research and Development, 10578 Science Center Drive, CB1, San Diego, CA 92121, USA. brett.houk@pfizer.com
authors.forename: Brett E
authors.initials: BE
authors.lastname: Houk
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Bello
authors.forename: Bill
authors.initials: B
authors.lastname: Poland
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology; D023381:Endpoint Determination; D005221:Fatigue / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D007958:Leukocyte Count; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects; D017711:Nonlinear Dynamics; D011153:Population; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib