Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue

Carlton K K Lee, Eric K. Rowinsky, Jing Li, Francis Giles, Malcolm J. Moore, Manuel Hidalgo, Edmund Capparelli, Jacques Jolivet, Sharyn D. Baker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2158-2165
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number7 I
DOIs
StatePublished - Apr 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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