title: Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.
abstract: BACKGROUND
  In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy.
  
  
  METHODS
  Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients.
  
  
  RESULTS
  Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival.
  
  
  CONCLUSIONS
  Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.
authors.affiliation: Lerner College of Medicine, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA rinib2@ccf.org.
authors.forename: B I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Departments of Genitourinary Oncology and Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Fishman
authors.affiliation: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Oya
authors.affiliation: Clinical Pharmacology/Clinical Development, Pfizer Oncology, San Diego, USA.
authors.forename: Y K
authors.initials: YK
authors.lastname: Pithavala
authors.affiliation: Clinical Pharmacology/Clinical Development, Pfizer Oncology, San Diego, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinical Pharmacology/Clinical Development, Pfizer Oncology, San Diego, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Bair
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Grünwald
mesh_terms: D000077784:Axitinib; D001794:Blood Pressure / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007191:Indazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib
keywords: axitinib; blood pressure; dose titration; pharmacokinetics; renal cell carcinoma