| Autor: |
Bonate, Peter L., Craig, Adam, Gaynon, Paul, Gandhi, Varsha, Jeha, Sima, Kadota, Richard, Lam, Gilbert N., Plunkett, William, Razzouk, Bassem, Rytting, Michael, Steinherz, Peter, Weitman, Steve |
| Zdroj: |
Journal of Clinical Pharmacology; Nov2004, Vol. 44 Issue 11, p1309-1322, 14p |
| Abstrakt: |
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. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
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