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 × 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-square-meter or per-body-weight basis.
Original language | English (US) |
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Pages (from-to) | 1309-1322 |
Number of pages | 14 |
Journal | Journal of Clinical Pharmacology |
Volume | 44 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2004 |
Keywords
- Acute lymphoblastic leukemia
- Acute myelogenous leukemia
- Clofarabine triphosphate
- Influence analysis
- Metabolite kinetics
- Model validation
- NONMEM
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)