title: Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia.
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.
authors.affiliation: ILEX Products, 4545 Horizon Hill Boulevard, San Antonio, TX 78229, USA.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
authors.forename: Adam
authors.initials: A
authors.lastname: Craig
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Richard
authors.initials: R
authors.lastname: Kadota
authors.forename: Gilbert N
authors.initials: GN
authors.lastname: Lam
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Bassem
authors.initials: B
authors.lastname: Razzouk
authors.forename: Michael
authors.initials: M
authors.lastname: Rytting
authors.forename: Peter
authors.initials: P
authors.lastname: Steinherz
authors.forename: Steve
authors.initials: S
authors.lastname: Weitman
mesh_terms: D000227:Adenine Nucleotides; D000293:Adolescent; D000328:Adult; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D000077866:Clofarabine; D003198:Computer Simulation; D006207:Half-Life; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D007958:Leukocyte Count; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D015203:Reproducibility of Results
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine