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Population Pharmacokinetics of Troxacitabine, a Novel Dioxolane Nucleoside Analogue

Authors' Affiliations: Departments of ¹ Oncology and ² Pediatrics, Johns Hopkins University and Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, Maryland; ³ The Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas; ⁴ The University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁵ Princess Margaret Hospital, Toronto, Ontario, Canada; ⁶ Pediatric Pharmacology Research Unit, University of California at San Diego, La Jolla, California; and ⁷ BioChem Pharma, Inc., Laval, Quebec, Canada

Requests for reprints: Sharyn D. Baker, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 1M86, Baltimore, MD 21231. Phone: 410-502-7149; Fax: 410-614-9006; E-mail: sbaker7{at}jhmi.edu.

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.

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