Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia

J Clin Pharmacol. 2004 Nov;44(11):1309-22. doi: 10.1177/0091270004269236.

Abstract

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 10(3)/microL), 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 microM (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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine Nucleotides
  • Adolescent
  • Adult
  • Arabinonucleosides / administration & dosage
  • Arabinonucleosides / pharmacokinetics*
  • Child
  • Child, Preschool
  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase II as Topic
  • Clofarabine
  • Computer Simulation
  • Half-Life
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukocyte Count
  • Metabolic Clearance Rate
  • Models, Biological
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Reproducibility of Results

Substances

  • Adenine Nucleotides
  • Arabinonucleosides
  • Clofarabine