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Population Pharmacokinetics of Clofarabine, a Second-Generation Nucleoside Analog, in Pediatric Patients With Acute Leukemia

From ILEX Products, San Antonio, Texas (Dr Bonate, Dr Craig, Dr Weitman); Children's Hospital of Los Angeles Outpatient Towers, Los Angeles, California (Dr Gaynon); University of Texas M. D. Anderson Cancer Center, Houston, Texas (Dr Gandhi, Dr Plunkett, Dr Rytting); St. Jude Children's Research Hospital, Memphis, Tennessee (Dr Jeha, Dr Razzouk); Children's Hospital of San Diego, Oncology Department, San Diego, California (Dr Kadota); MicroConstants, Inc, San Diego, California (Dr Lam); and Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, New York (Dr Steinherz). Dr Craig's current affiliation is Arqule, Inc, Woburn, Massachusetts.

The population pharmacokinetics of plasma clofarabine and intracellular clofarabine triphosphate were characterized in pediatric patients with acute leukemias. Traditional model-building techniques with NONMEM were used. Covariates were entered into the base model using a forward selection significance level of .05 and a backwards deletion criterion of .005. Model performance, stability, and influence analysis were assessed using the nonparametric bootstrap and n-1 jackknife. Simulations were used to understand the relationship between important covariates and exposure. A 2-compartment model with weight (scaled to a 40-kg reference patient) modeled as a power function on all pharmacokinetic parameters (0.75 on clearance-related terms and 1.0 on volume-related terms) was fit to plasma clofarabine concentrations (n = 32). White blood cell (WBC) count, modeled as a power function (scaled to a WBC count of 10 x 10³/µL), was a significant predictor of central volume with power term 0.128 ± 0.0314. A reference patient had a systemic clearance of 32.8 L/h (27% between-subject variability [BSV]), a central volume of 115 L (56% BSV), an intercompartmental clearance of 20.5 L/h (27% BSV), and a peripheral volume of 94.5 L (39% BSV). Intracellular clofarabine triphosphate concentrations were modeled using a random intercept model without any covariates. The average predicted concentration was 11.6 ± 2.62 µM (80% BSV), and although clofarabine triphosphate half-life could not be definitively estimated, its value was taken to be longer than 24 hours. The results confirm that clofarabine should continue being dosed on a per-squaremeter or per-body-weight basis.

Key Words: NONMEM • acute lymphoblastic leukemia • acute myelogenous leukemia • influence analysis • metabolite kinetics • model validation • clofarabine triphosphate

Address for reprints: Peter L. Bonate, ILEX Products, 4545 Horizon Hill Boulevard, San Antonio, TX 78229.

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