title: Evaluation of satraplatin in dogs with spontaneously occurring malignant tumors.
abstract: BACKGROUND
  Satraplatin is the 1st orally bioavailable platinum anticancer drug.
  
  
  OBJECTIVE
  Our objectives were to evaluate efficacy in vitro against a canine cancer cell line, to determine the maximally tolerated dose (MTD) of satraplatin in tumor-bearing dogs, to identify the dose-limiting and other toxicities in dogs, and to record pharmacokinetics (PK).
  
  
  METHODS
  Dogs with macro- or microscopic malignant neoplasia.
  
  
  METHODS
  D17 canine osteosarcoma cells first were evaluated in a clonogenic survival assay. Then, dogs with a diagnosis of malignant neoplasia were prospectively entered in standard 3 + 3 cohorts. Additional patients were entered at the MTD to assess efficacy. Total and free platinum (by ultrafiltrate) concentrations were determined with inductively coupled plasma mass spectroscopy.
  
  
  RESULTS
  Satraplatin inhibited clonogenic survival in vitro at clinically relevant and achievable concentrations. Twenty-three dogs were treated, 14 with PK evaluation. The MTD was 35 mg/m(2)/d for 5 days, repeated every 3-4 weeks. Bioavailability was 41%. PK variables (mean ± SD) at the MTD included T(max) 1.8 (± 0.7) hours, C(max) 72 (± 26) ng/mL, area under concentration (AUC)(0-24 h) 316 (± 63) h × ng/mL, and MRT 7 (± 1.3) hours. Higher AUC after the 5th versus the 1st dose suggested drug accumulation. Interestingly, platelets consistently reached nadir sooner than did neutrophils (day 14 versus 19). Myelosuppression was dose-limiting and gastrointestinal toxicity was mild.
  
  
  CONCLUSIONS
  Satraplatin was well tolerated in tumor-bearing dogs, thus warranting further investigation in a phase II trial.
authors.affiliation: Department of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA. seltingk@missouri.edu
authors.forename: K A
authors.initials: KA
authors.lastname: Selting
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: D L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: C J
authors.initials: CJ
authors.lastname: Henry
authors.forename: J A
authors.initials: JA
authors.lastname: Villamil
authors.forename: D L
authors.initials: DL
authors.lastname: McCaw
authors.forename: D
authors.initials: D
authors.lastname: Tate
authors.forename: M
authors.initials: M
authors.lastname: Beittenmiller
authors.forename: C
authors.initials: C
authors.lastname: Garnett
authors.forename: J D
authors.initials: JD
authors.lastname: Robertson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin