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

Peter L. Bonate, Adam Craig, Paul Gaynon, Varsha Gandhi, Sima Jeha, Richard Kadota, Gilbert N. Lam, William Plunkett, Bassem Razzouk, Michael Rytting, Peter Steinherz, Steven D Weitman

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1309-1322
Number of pages14
JournalJournal of Clinical Pharmacology
Volume44
Issue number11
DOIs
StatePublished - Nov 2004
Externally publishedYes

Fingerprint

Nucleosides
Leukemia
Pharmacokinetics
Pediatrics
Population
Leukocyte Count
Half-Life
clofarabine
Body Weight
Weights and Measures
triphosphoric acid

Keywords

  • Acute lymphoblastic leukemia
  • Acute myelogenous leukemia
  • Clofarabine triphosphate
  • Influence analysis
  • Metabolite kinetics
  • Model validation
  • NONMEM

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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

In: Journal of Clinical Pharmacology, Vol. 44, No. 11, 11.2004, p. 1309-1322.

Research output: Contribution to journalArticle

Bonate, PL, Craig, A, Gaynon, P, Gandhi, V, Jeha, S, Kadota, R, Lam, GN, Plunkett, W, Razzouk, B, Rytting, M, Steinherz, P & Weitman, SD 2004, 'Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia', Journal of Clinical Pharmacology, vol. 44, no. 11, pp. 1309-1322. https://doi.org/10.1177/0091270004269236
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, Steven D. / Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia. In: Journal of Clinical Pharmacology. 2004 ; Vol. 44, No. 11. pp. 1309-1322.
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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.",
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