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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 5/2012

01-05-2012 | Original Article

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

Authors: Mikkel Krogh-Madsen, Brendan Bender, Morten Krogh Jensen, Ove Juul Nielsen, Lena E. Friberg, Per Hartvig Honoré

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2012

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Abstract

Purpose

Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area–adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and give insights into the PK of this combination treatment.

Methods

A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM®; for daunorubicin, PK information from a prior study was utilized.

Results

Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included. The volume increased 1.9% for each increase in bWBC by 1 × 106 cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%.

Conclusions

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.
Literature
1.
2.
Burnett A, Wetzler M, Lowenberg B (2011) Therapeutic advances in acute myeloid leukemia. J Clin Oncol 29(5):487–494PubMedCrossRef
3.
Cros E, Jordheim L, Dumontet C, Galmarini CM (2004) Problems related to resistance to cytarabine in acute myeloid leukemia. Leuk Lymphoma 45(6):1123–1132PubMedCrossRef
4.
Hiddemann W (1991) Cytosine arabinoside in the treatment of acute myeloid leukemia: the role and place of high-dose regimens. Ann Hematol 62(4):119–128PubMedCrossRef
5.
Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P (2001) Antineoplastic Agents. In: Hardman JG, Limbird LE, Gilman AG (eds) The pharmacological basis of therapeutics, 10th edn. McGraw-Hill, New York, pp 1389–1460
6.
Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521PubMedCrossRef
7.
Rabbani A, Finn RM, Ausio J (2005) The anthracycline antibiotics: antitumor drugs that alter chromatin structure. Bioessays 27(1):50–56PubMedCrossRef
8.
Richardson DS, Johnson SA (1997) Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. Blood Rev 11(4):201–223PubMedCrossRef
9.
Robert J, Gianni L (1993) Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219–252PubMed
10.
Robert J (2005) Anthracyclines. In: Schellens JH, McLeod H, Newell DR (eds) Cancer Clinical Pharmacology, 1st edn. Oxford University Press, Oxford, pp 117–133
11.
Bogason A, Quartino AL, Lafolie P et al (2011) Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloid leukaemia. Br J Clin Pharmacol 71(4):514–521PubMedCrossRef
12.
Fleming RA, Capizzi RL, Rosner GL et al (1995) Clinical pharmacology of cytarabine in patients with acute myeloid leukemia: a cancer and leukemia group B study. Cancer Chemother Pharmacol 36(5):425–430PubMedCrossRef
13.
Burk M, Heyll A, Arning M, Volmer M, Fartash K, Schneider W (1997) Pharmacokinetics of high-dose cytarabine and its deamination product–a reappraisal. Leuk Lymphoma 27(3–4):321–327PubMedCrossRef
14.
You B, Tranchand B, Girard P et al (2008) Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study. Lung Cancer 62(2):261–272PubMedCrossRef
15.
Nguyen L, Chatelut E, Chevreau C et al (1998) Population pharmacokinetics of total and unbound etoposide. Cancer Chemother Pharmacol 41(2):125–132PubMedCrossRef
16.
Wilde S, Jetter A, Rietbrock S et al (2007) Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin’s lymphoma and its effect on myelotoxicity. Clin Pharmacokinet 46(4):319–333PubMedCrossRef
17.
Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28(5):481–504PubMedCrossRef
18.
Gisleskog PO, Karlsson MO, Beal SL (2002) Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn 29(5–6):473–505PubMedCrossRef
19.
Krogh-Madsen M, Hansen SH, Honore PH (2010) Simultaneous determination of cytosine arabinoside, daunorubicin and etoposide in human plasma. J Chromatogr B Anal Technol Biomed Life Sci 878(22):1967–1972CrossRef
20.
Ahn JE, Karlsson MO, Dunne A, Ludden TM (2008) Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn 35(4):401–421PubMedCrossRef
21.
Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11(2):371–380PubMedCrossRef
22.
Bonate PL (2006) Pharmacokinetic-pharmacodynamic modeling and simulation. Springer, New York
23.
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41PubMedCrossRef
24.
Kroschinsky FP, Friedrichsen K, Mueller J et al (2008) Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas. Cancer Chemother Pharmacol 61(5):785–790PubMedCrossRef
25.
Burgio DE, Gosland MP (1998) McNamara a. Effects of P-glycoprotein modulators on etoposide elimination and central nervous system distribution. J Pharmacol Exp Ther 287(3):911–917PubMed
26.
Rustum YM, Raymakers RA (1992) 1-Beta-arabinofuranosylcytosine in therapy of leukemia: preclinical and clinical overview. Pharmacol Ther 56(3):307–321PubMedCrossRef
27.
Andersson B, Beran M, Peterson C, Tribukait B (1982) Significance of cellular pharmacokinetics for the cytotoxic effects of daunorubicin. Cancer Res 42(1):178–183PubMed
28.
van den Bongard HJ, Mathot RA, Beijnen JH, Schellens JH (2000) Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet 39(5):345–367PubMedCrossRef
29.
Panteghini M, Myers GL, Miller WG, Greenberg N (2006) The importance of metrological traceability on the validity of creatinine measurement as an index of renal function. Clin Chem Lab Med 44(10):1287–1292PubMedCrossRef
30.
Kirkpatrick CM, Duffull SB, Begg EJ (1999) Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol 47(6):637–643PubMedCrossRef
31.
Fesler P, Mimran A (2011) Estimation of glomerular filtration rate: what are the pitfalls? Curr Hypertens Rep 13(2):116–121PubMedCrossRef
32.
Salgado JV, Neves FA, Bastos MG et al (2010) Monitoring renal function: measured and estimated glomerular filtration rates—a review. Braz J Med Biol Res 43(6):528–536PubMedCrossRef
33.
Mould DR, Holford NH, Schellens JH et al (2002) Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther 71(5):334–348PubMedCrossRef
34.
McLeod HL, Evans WE (1993) Clinical pharmacokinetics and pharmacodynamics of epipodophyllotoxins. Cancer Surv 17:253–268PubMed
35.
Hartmann JT, Lipp HP (2006) Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II—mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf 29(3):209–230PubMedCrossRef
36.
Kaul S, Srinivas NR, Mummaneni V, Igwemezie LN, Barbhaiya RH (1996) Effects of gender, age, and race on the pharmacokinetics of etoposide after intravenous administration of etoposide phosphate in cancer patients. Semin Oncol 23(6 Suppl 13):23–29PubMed
Metadata
Title
Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia
Authors
Mikkel Krogh-Madsen
Brendan Bender
Morten Krogh Jensen
Ove Juul Nielsen
Lena E. Friberg
Per Hartvig Honoré
Publication date
01-05-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 5/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1800-z

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