title: Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs.
abstract: BACKGROUND
  Paclitaxel is highly effective in the treatment of many cancers in humans, but cannot be routinely used in dogs as currently formulated due to the exquisite sensitivity of this species to surfactant-solubilizing agents. CTI 52010 is a formulation of nanoparticulate paclitaxel consisting of drug and normal saline. Our objectives were to determine the maximally tolerated dose, dose-limiting toxicities, and pharmacokinetics of CTI 52010 administered intravenously to normal dogs.
  
  
  METHODS
  Three normal adult hound dogs were evaluated by physical examination, complete blood count, chemistry profile, and urinalysis. Dogs were treated with staggered escalating dosages of CTI 52010 with a 28-day washout. All dogs were treated with a starting dosage of 40 mg/m(2), and subsequent dosages were escalated at 50% (dog 1), 100% (dog 2), or 200% (dog 3) with each cycle, to a maximum of 240 mg/m(2). Dogs were monitored by daily physical assessment and weekly laboratory evaluation. Standard criteria were used to grade adverse events. Plasma was collected at regular intervals to determine pharmacokinetics. Dogs were euthanized humanely, and necropsy was performed one week after the last treatment.
  
  
  RESULTS
  The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m(2). Grade 1-2 gastrointestinal toxicity was noted at higher dosages. Upon post mortem evaluation, no evidence of organ (liver, kidney, spleen) toxicity was noted.
  
  
  CONCLUSIONS
  CTI 52010 was well tolerated when administered intravenously to normal dogs. A starting dosage for a Phase I/II trial in tumor-bearing dogs is 80 mg/m(2).
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Axiak
authors.forename: Kim A
authors.initials: KA
authors.lastname: Selting
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Decedue
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Henry
authors.forename: Deborah
authors.initials: D
authors.lastname: Tate
authors.forename: Jahna
authors.initials: J
authors.lastname: Howell
authors.forename: K James
authors.initials: KJ
authors.lastname: Bilof
authors.forename: Dae Y
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic / Q000662:veterinary; D004283:Dog Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004285:Dogs; D016503:Drug Delivery Systems; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects*; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D013154:Spleen / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
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