Pharmacokinetics of High-Dose Cytarabine and its Deamination Product-A Reappraisal

Abstract

Cytarabine is intracellularly activated and correlations have been established between the pharmacokinetic behaviour of active metabolites and their antileukemic effect. Recently, a good response to high-dose treatment of leukemias has additionally been attributed to a so-called low deamination phenotype of cytarabine inactivation. Consequently, these findings would support plasma level monitoring of cytarabine and its metabolite uracil arabinoside in high-dose cytarabine regimens. This pharmacokinetic study presents data attempting to reevaluate these observations. Thirty-seven patients were treated by 3-h high-dose cytarabine infusions (9 patients 1000 mg/m2, 28 patients 3000 mg/m2) as part of their treatment for acute leukemia. Serial blood samples during and post infusion were analysed for cytarabine (araC) and its deamination product uracil arabinoside (araU) using HPLC with UV-detection. Considerable interindividual variation was observed in end-infusion plasma concentrations of araC (1000 mg/m2: 2.1-fold, 3000 mg/m2: 5.5-fold) and araU (1000 mg/m2: 2.7-fold, 3000 mg/m2: 2.9-fold). The median ratio of end infusion concentrations araU/araC (on a molar basis) was 5.6 (S.D. 3.0), extreme ratio values were 2 and 14. No differences of the araU/araC ratio were found between the two dosages used. Minimum plasma araC concentrations at the end of infusion were 10.5 micromol/l and 22.0 micromol/l at a dose of 1000 and 3000 mg/m2, respectively. In our European study population a "fast" deamination phenotype of cytarabine (araU/araC ratio > 14) was not be observed.

Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia

“…In the present study, four of the twenty-three patients had bWBC above 70 9 10 6 cells/mL. Gender was a significant covariate for Ara-C clearance in the present study and has also previously been included in patients with AML [12,13]. In spite of this, it was not included in the final model.…”

“…Interestingly, a similar effect has been described for Ara-C in a constant infusion regimen [12], whereas other investigators did not find this correlation for patients receiving higher doses of Ara-C (1,000-3,000 mg/m 2 ) [13]. Studies in other types of cancer have shown a correlation between serum creatinine (se-Cr) [14,15] or calculated creatinine clearance (cCrCL) [16] and etoposide PK parameters, thus advocating that kidney function should be considered when dosing etoposide.…”

“…The evidence is diluted by the fact that the two previous studies provide conflicting data. The study by Burk et al [13], with high-dose, 3-h infusion Ara-C treatment, found an increased CL in female patients, and Fleming et al [12], with intermediate dose, continuous infusion Ara-C, found an increased CL in the male population. Weight may in part explain gender differences, but neither study included weight as a covariate.…”

Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

“…However, clinical outcome is unsatisfactory, as most of the patients who achieve a complete remission will relapse within 2 years from diagnosis, often with resistant disease and poor response to subsequent therapy. 2,3 Insufficient activity of first-line chemotherapy therefore remains a major obstacle in the effective treatment of patients with AML. Understanding the factors that contribute to the emergence of chemoresistant leukemic cells is essential to improve outcome in patients with AML.…”

AraU accumulation in patients with renal insufficiency as a potential mechanism for cytarabine neurotoxicity

“…Plasma levels of AraC throughout high-dose infusion (1-3 g/m 2 ) in patients with normal renal and liver function are well investigated and reported as 10 up to 115 lM [27,[31][32][33] depending on the dose and the infusion time. Upon cessation of infusion, AraC is rapidly cleared from the plasma with a terminal half-life of about 1-3 h [31,[33][34][35].…”