Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue Academic Article Article uri icon

Overview

MeSH Major

  • Neoplasm Transplantation
  • Neoplasms
  • Neoplasms, Experimental
  • Transplantation, Heterologous

abstract

  • Purpose: To develop and validate a population pharmacokinetic model for troxacitabine, a novel L-nucleoside analogue, administered by short infusion; to characterize clinical covariates that influence pharmacokinetic variability; and to design a dosage rate for continuous infusion administration to achieve low micromolar concentrations, which may be more efficacious than shorter infusions. Experimental Design: Plasma samples from 111 cancer patients receiving troxacitabine (0.12-12.5 mg/m2) as a 30-minute infusion in phase I trials were used to develop the model with NONMEM. Clinical covariates evaluated included creatinine clearance, body surface area, age, and sex. From the model, a troxacitabine dosage rate of 2.0 to 3.0 mg/m2/d was expected to achieve a target concentration of 0.1 μmol/L; plasma samples were obtained during the infusion from eight patients receiving troxacitabine as a 3-day infusion. Results: Troxacitabine pharmacokinetics were characterized by a three-compartment linear model. The mean value for systemic clearance [interindividual variability (CV%)] from the covariate-free model was 9.1 L/h (28%). Creatinine clearance and body surface area accounted for 36% of intersubject variation in clearance. Troxacitabine 2.0 mg/m2/d (n = 3) and 3.0 mg/m2/d (n = 5) for 3 days produced mean ± SD end of infusion concentrations of 0.12 ± 0.03 and 0.15 ± 0.03 μmol/L, respectively. Conclusions: Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability. The population pharmacokinetic model model - derived dosage rates for continuous infusion administration successfully achieved predetermined target plasma concentrations. The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size. © 2006 American Association for Cancer Research.

publication date

  • April 2006

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-05-2249

PubMed ID

  • 16609029

Additional Document Info

start page

  • 2158

end page

  • 2165

volume

  • 12

number

  • 7 I