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Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the children's oncology group.

McCune, Jeannine S and Salinger, David H and Vicini, Paolo and Oglesby, Celeste and Blough, David K and Park, Julie R (2009) Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the children's oncology group. Journal of clinical pharmacology, 49 (1). pp. 88-102. ISSN 0091-2700

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Article URL: http://jcp.sagepub.com/cgi/reprint/49/1/88

Abstract

Cyclophosphamide-based regimens are front-line treatment for numerous pediatric malignancies; however, current dosing methods result in considerable interpatient variability in tumor response and toxicity. In this pediatric population, the authors' objectives were (1) to quantify and explain the pharmacokinetic variability of cyclophosphamide and 2 of its metabolites, hydroxycyclophosphamide (HCY) and carboxyethylphosphoramide mustard (CEPM), and (2) to apply a population pharmacokinetic model to describe the disposition of cyclophosphamide and these metabolites. A total of 196 blood samples were obtained from 22 children with neuroblastoma receiving intravenous cyclophosphamide (400 mg/m2/d) and topotecan. Blood samples were quantitated for concentrations of cyclophosphamide, HCY, and CEPM using liquid chromatography-mass spectrometry and analyzed using nonlinear mixed-effects modeling with the NONMEM software system. After model building was complete, the area under the concentration-time curve (AUC) was computed using NONMEM. Cyclophosphamide elimination was described by noninducible and inducible routes, with the latter producing HCY. Glomerular filtration rate was a covariate for the fractional elimination of HCY and its conversion to CEPM. Considerable interpatient variability was observed in the AUC of cyclophosphamide, HCY, and CEPM. These results represent a critical first step in developing pharmacokinetic-linked pharmacodynamic studies in children receiving cyclophosphamide to determine the clinical relevance of the pharmacokinetic variability in cyclophosphamide and its metabolites.

Item Type: Article
Additional Information: This article is available to subscribers only via the URL above.
DOI: 10.1177/0091270008325928
PubMed ID: 18927240
NIHMSID: NIHMS94095
PMCID: PMC2652687
Grant Numbers: P01 CA018029-33, K23 CA087058-01A2, U10 CA098543-06, P41 EB001975-10, M01 RR000037-47
Keywords or MeSH Headings: * Antineoplastic Agents, Alkylating/pharmacokinetics* * Antineoplastic Agents, Alkylating/therapeutic use * Child * Child, Preschool * Cyclophosphamide/analogs & derivatives * Cyclophosphamide/metabolism * Cyclophosphamide/pharmacokinetics* * Cyclophosphamide/therapeutic use * Female * Humans * Infant * Male * Models, Biological * Neuroblastoma/drug therapy* * Phosphoramide Mustards/metabolism
Subjects: Diseases > Solid tumors > Brain cancer
Therapeutics > Drug Therapy
Depositing User: Library Staff
Date Deposited: 09 Feb 2009 20:21
Last Modified: 14 Feb 2012 14:42
URI: http://authors.fhcrc.org/id/eprint/247

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