title: Species differences in troxacitabine pharmacokinetics and pharmacodynamics: implications for clinical development.
abstract: OBJECTIVE
  Troxacitabine is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models.
  
  
  METHODS
  Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of [14C]troxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules.
  
  
  RESULTS
  Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring >24 hours exposure for maximum activity. Analysis of the intracellular metabolites of [14C]troxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 micromol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity [treated versus control (T/C) of 27% and tumor regression during treatment].
  
  
  CONCLUSIONS
  These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
authors.affiliation: Shire BioChem Inc., Laval, Quebec, Canada.
authors.forename: Henriette
authors.initials: H
authors.lastname: Gourdeau
authors.forename: Lorraine
authors.initials: L
authors.lastname: Leblond
authors.forename: Bettina
authors.initials: B
authors.lastname: Hamelin
authors.forename: Kelly
authors.initials: K
authors.lastname: Dong
authors.forename: France
authors.initials: F
authors.lastname: Ouellet
authors.forename: Chantal
authors.initials: C
authors.lastname: Boudreau
authors.forename: Dominique
authors.initials: D
authors.lastname: Custeau
authors.forename: Annie
authors.initials: A
authors.lastname: Richard
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Gilbert
authors.forename: Jacques
authors.initials: J
authors.lastname: Jolivet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004148:Dioxolanes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006412:Hematopoietic Stem Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine