Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ADE:

Cytarabine + Daunorubicin + Etoposide treatment

ALAT:

Alanine aminotransferase

AML:

Acute myeloid leukemia

Ara-C:

Cytosine arabinoside

BLQ:

Below limit of quantification

BSA:

Body surface area

bWBC:

Baseline white blood cell count

cCrCL:

Calculated creatinine clearance

Dnr:

Daunorubicin

Eto:

Etoposide

HPLC:

High-pressure liquid chromatography

LLoQ:

Lower limit of quantification

OFV:

Objective function value

PK:

Pharmacokinetic

RSE:

Relative standard error

SCM:

Stepwise covariate modeling

SD:

Standard deviation

Se-Cr:

Serum creatinine

v :

Degrees of freedom

VPC:

Visual predictive check

References

  1. Estey E, Dohner H (2006) Acute myeloid leukaemia. Lancet 368(9550):1894–1907

    Article  PubMed  Google Scholar 

  2. Burnett A, Wetzler M, Lowenberg B (2011) Therapeutic advances in acute myeloid leukemia. J Clin Oncol 29(5):487–494

    Article  PubMed  Google Scholar 

  3. Cros E, Jordheim L, Dumontet C, Galmarini CM (2004) Problems related to resistance to cytarabine in acute myeloid leukemia. Leuk Lymphoma 45(6):1123–1132

    Article  PubMed  CAS  Google Scholar 

  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):119–128

    Article  PubMed  CAS  Google Scholar 

  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

    Google Scholar 

  6. Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521

    Article  PubMed  CAS  Google Scholar 

  7. Rabbani A, Finn RM, Ausio J (2005) The anthracycline antibiotics: antitumor drugs that alter chromatin structure. Bioessays 27(1):50–56

    Article  PubMed  CAS  Google Scholar 

  8. Richardson DS, Johnson SA (1997) Anthracyclines in haematology: preclinical studies, toxicity and delivery systems. Blood Rev 11(4):201–223

    Article  PubMed  CAS  Google Scholar 

  9. Robert J, Gianni L (1993) Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219–252

    PubMed  CAS  Google Scholar 

  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

    Google Scholar 

  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):514–521

    Article  PubMed  CAS  Google Scholar 

  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):425–430

    Article  PubMed  CAS  Google Scholar 

  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):321–327

    Article  PubMed  CAS  Google Scholar 

  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):261–272

    Article  PubMed  Google Scholar 

  15. Nguyen L, Chatelut E, Chevreau C et al (1998) Population pharmacokinetics of total and unbound etoposide. Cancer Chemother Pharmacol 41(2):125–132

    Article  PubMed  CAS  Google Scholar 

  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):319–333

    Article  PubMed  CAS  Google Scholar 

  17. Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28(5):481–504

    Article  PubMed  CAS  Google Scholar 

  18. Gisleskog PO, Karlsson MO, Beal SL (2002) Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn 29(5–6):473–505

    Article  PubMed  Google Scholar 

  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):1967–1972

    Article  CAS  Google Scholar 

  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):401–421

    Article  PubMed  Google Scholar 

  21. Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11(2):371–380

    Article  PubMed  CAS  Google Scholar 

  22. Bonate PL (2006) Pharmacokinetic-pharmacodynamic modeling and simulation. Springer, New York

    Google Scholar 

  23. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41

    Article  PubMed  CAS  Google Scholar 

  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):785–790

    Article  PubMed  CAS  Google Scholar 

  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):911–917

    PubMed  CAS  Google Scholar 

  26. Rustum YM, Raymakers RA (1992) 1-Beta-arabinofuranosylcytosine in therapy of leukemia: preclinical and clinical overview. Pharmacol Ther 56(3):307–321

    Article  PubMed  CAS  Google Scholar 

  27. Andersson B, Beran M, Peterson C, Tribukait B (1982) Significance of cellular pharmacokinetics for the cytotoxic effects of daunorubicin. Cancer Res 42(1):178–183

    PubMed  CAS  Google Scholar 

  28. van den Bongard HJ, Mathot RA, Beijnen JH, Schellens JH (2000) Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet 39(5):345–367

    Article  PubMed  Google Scholar 

  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):1287–1292

    Article  PubMed  CAS  Google Scholar 

  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):637–643

    Article  PubMed  CAS  Google Scholar 

  31. Fesler P, Mimran A (2011) Estimation of glomerular filtration rate: what are the pitfalls? Curr Hypertens Rep 13(2):116–121

    Article  PubMed  Google Scholar 

  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):528–536

    Article  PubMed  CAS  Google Scholar 

  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):334–348

    Article  PubMed  CAS  Google Scholar 

  34. McLeod HL, Evans WE (1993) Clinical pharmacokinetics and pharmacodynamics of epipodophyllotoxins. Cancer Surv 17:253–268

    PubMed  CAS  Google Scholar 

  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):209–230

    Article  PubMed  CAS  Google Scholar 

  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):23–29

    PubMed  CAS  Google Scholar 

Web references

  1. [webA] AML 17 trial protocol: http://aml17.cardiff.ac.uk/files/new2/AML%2017%20Protocol%20V5.0%20May%202010.pdf; Accessed July 15, 2011

  2. [webB] AML 15 trial protocol: http://www.download.bham.ac.uk/bctu/AML15/Amendment%20Nov%202007/AML15%20protocol%20version%207%20Final%20200704201%20with%20no%20track%20changes.pdf; Accessed July 15, 2011

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark

    Mikkel Krogh-Madsen & Per Hartvig Honoré

  2. Department of Pharmaceutical Biosciences, Pharmacometrics Research Group, Uppsala University, 751 24, Uppsala, Sweden

    Brendan Bender & Lena E. Friberg

  3. Department of Haematology L-124, Herlev Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark

    Morten Krogh Jensen

  4. Department of Haematology L-4042, Rigshospitalet, Blegdamsvej, 2100, Copenhagen, Denmark

    Ove Juul Nielsen

Authors
  1. Mikkel Krogh-Madsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendan Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Morten Krogh Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ove Juul Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lena E. Friberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Per Hartvig Honoré
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mikkel Krogh-Madsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krogh-Madsen, M., Bender, B., Jensen, M.K. et al. Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia. Cancer Chemother Pharmacol 69, 1155–1163 (2012). https://doi.org/10.1007/s00280-011-1800-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1800-z

Keywords

Search

Navigation