title: Pharmacology studies of 1-beta-D-arabinofuranosylcytosine in pediatric patients with leukemia and lymphoma after a biochemically optimal regimen of loading bolus plus continuous infusion of the drug.
abstract: In an attempt to maximize the therapeutic index and to overcome the large variations in 1-beta-D-arabinofuranosylcytosine (ara-C) plasma levels and host toxicities that have been documented with standard HDara-C regimens (3 g/m2 over 3 h every 12 h x 8 or x12 doses), pediatric patients with acute lymphocytic leukemia or lymphoma in relapse were treated with a regimen of loading bolus followed immediately by continuous infusion of ara-C. In addition, patients received a single dose of etoposide (VP-16, 1 g/m2) prior to the ara-C administration. In four patients, total body irradiation was administered as part of a bone marrow transplantation preparative regimen after the ara-C administration. The regimen was designed to attain and maintain plasma steady-state concentrations (Css) of ara-C three to four times the Km2 value of ara-C, which was determined with purified deoxycytidine kinase from the patients' tumor cells prior to treatment. Eight patients age 0.75 to 16 years with relapsed acute lymphocytic leukemia (three patients) or lymphoma (five patients, one with bone marrow involvement), received a test dose of 3 g/m2 ara-C injected over 1 h, and the plasma kinetics were determined. The peak plasma ara-C concentration of ara-C ranged from 57 to 199 microM with an average concentration of 103 +/- 49 microM; the half-lives of distribution (t1/2, alpha) and elimination (t1/2, beta) averaged 17 +/- 7 min and 4.04 +/- 3.1 h, respectively. The mean area under the plasma concentration time curve from 0 to 12 h (AUC0----12 h) of ara-C averaged 386.8 +/- 328.0 microMh (mean, +/- SD, n = 8). The peak concentration of uracil arabinoside averaged 501 +/- 123 microM, and it was eliminated with a t1/2, el of 2.3 +/- 0.6 h. The patients then received an individualized loading bolus (mean = 0.5 g/m2) followed by a continuous infusion regimen of ara-C (mean = 130 mg/m2/h), to achieve a Css in the range of 20 to 35 microM. The obtained plasma Css were similar to the desired ones, averaging in variation 10.7% +/- 8.2%. The percentage of variation of correlation of the AUC following the loading bolus plus the continuous infusion from 12 to 72 h was only 12.4% (mean = 2158 microMh, n = 8), whereas the percentage of variation of correlation of the AUC after the test dose of ara-C in the same patients was 84.8%.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pediatrics, School of Medicine, University of Southern California, Childrens Hospital of Los Angeles 90027.
authors.forename: V I
authors.initials: VI
authors.lastname: Avramis
authors.forename: K I
authors.initials: KI
authors.lastname: Weinberg
authors.forename: J K
authors.initials: JK
authors.lastname: Sato
authors.forename: C
authors.initials: C
authors.lastname: Lenarsky
authors.forename: M L
authors.initials: ML
authors.lastname: Willoughby
authors.forename: T D
authors.initials: TD
authors.lastname: Coates
authors.forename: M F
authors.initials: MF
authors.lastname: Ozkaynak
authors.forename: R
authors.initials: R
authors.lastname: Parkman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003842:Deoxycytidine Kinase / Q000032:analysis; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*
chemical_list: D003561:Cytarabine; D003842:Deoxycytidine Kinase