title: Evaluation of the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases.
abstract: OBJECTIVE
  This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases.
  
  
  METHODS
  A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined.
  
  
  RESULTS
  Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC(0-12 h) was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean C(max) values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of -43.4 percent (200-mg group) and -34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group).
  
  
  CONCLUSIONS
  MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study.
authors.affiliation: Royal Melbourne Hospital, Melbourne, Australia. mark.rosenthal@mh.org.au
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: Peter
authors.initials: P
authors.lastname: Davidson
authors.forename: Frederic
authors.initials: F
authors.lastname: Rolland
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Lingling
authors.initials: L
authors.lastname: Xue
authors.forename: Tae H
authors.initials: TH
authors.lastname: Han
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Berd
authors.forename: Weili
authors.initials: W
authors.lastname: He
authors.forename: Antonio
authors.initials: A
authors.lastname: Lombardi
mesh_terms: D000368:Aged; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects*; D004311:Double-Blind Method; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D050071:Bone Density Conservation Agents; D016023:Integrins; D017430:Prostate-Specific Antigen