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

Burk, M.; Heyll, A.; Arning, M.; Volmer, M.; Fartash, Kamiar; Schneider, Wolfgang Ludwig

doi:10.3109/10428199709059686

Cited by 26 publications

(23 citation statements)

References 14 publications

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“…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.…”

Section: Discussionmentioning

confidence: 65%

“…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.…”

Section: Introductionmentioning

confidence: 56%

“…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.…”

Section: Discussionmentioning

confidence: 96%

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

Krogh-Madsen

Bender

Jensen

et al. 2012

Cancer Chemother Pharmacol

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Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 96%

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

Krogh-Madsen

Bender

Jensen

et al. 2012

Cancer Chemother Pharmacol

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Galmarini

Graham

Thomas

et al. 2001

Blood

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Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML. High Km 5NT was expressed at diagnosis in the blast cells of 54% of patients. In univariate analysis, (1) patients whose blast cells contained high levels (values greater than the median value for total population) of high Km 5NT at diagnosis had significantly shorter disease-free survival (DFS) than patients with low levels of high Km 5NT (11 months versus 17.5 months, P ‫؍‬ .02) and (2) high levels of high Km 5NT also predicted significantly shorter overall survival (15.7 months versus 39 months, P ‫؍‬ .01) in young patients (< 57 years; median value for the entire population). In a multivariate analysis taking into account age, karyotype risk, and other factors found to have prognostic significance in univariate analysis, (1) high Km 5NT expression was an independent prognostic factor for DFS and (2) high levels of high Km 5NT also predicted significantly shorter overall survival in young patients. These results demonstrate that the expression of high levels of high Km 5NT in blast cells is correlated with outcome in patients with AML. (Blood. 2001;98: 1922-1926

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Lindner¹,

Ostermann²,

Hiddemann³

et al. 2008

Int J Hematol

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Neurotoxicity of cytarabine (AraC) is believed to be related to renal insufficiency. We examined the plasma pharmacokinetics of AraC and its deamination product uracil arabinoside (AraU) in four patients with AML and concomitant severe renal insufficiency after treatment with AraC. Additionally, in one of these patients the concentration of intracellular AraCTP, the active metabolite of AraC, was analysed. Patients 2 and 3 were treated with AraC 1.0 g/m(2) infused for 3 h at 12-h intervals on days 1-4. Patient 1 received the same schedule of AraC with 0.5 g/m(2) and patient 4 with 0.25 g/m(2) AraC. Plasma concentrations of AraC, AraU and the intracellular concentration of AraCTP were analysed at different time points using HPLC. AraC pharmacokinetics in patients with severe renal insufficiency was comparable to patients with normal renal function. Peak plasma levels as well as intracellular AraCTP kinetics were also not significantly influenced by renal dysfunction. As expected from the high dose AraC pharmacokinetic parameters, the AraU serum levels accumulated during treatment. Under the conditions of renal impairment, AraU half-life was about 75 h and the AUC was about 12-fold higher than for patients with normal renal function. AraU could be the pathophysiologic cause for the known correlation between the incidence of neurotoxicity and renal insufficiency in high-dose AraC. To avoid AraU accumulation, intermittent hemodialysis during high-dose AraC treatment could be a suitable method considering the low protein-binding and low distribution volume of AraU.

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

Cited by 26 publications

References 14 publications

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

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

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

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

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