Clinical Pharmacokinetics

, Volume 57, Issue 3, pp 379–392 | Cite as

Population Pharmacokinetics of Volasertib Administered in Patients with Acute Myeloid Leukaemia as a Single Agent or in Combination with Cytarabine

  • Belén P. Solans
  • Angèle Fleury
  • Matthias Freiwald
  • Holger Fritsch
  • Karin Haug
  • Iñaki F. Trocóniz
Original Research Article



Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia.


The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination.


Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters.


The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other.


The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration–time curve.


Compliance with Ethical Standards


This work has been funded by Boehringer Ingelheim GmbH & Co.KG.

Conflict of interest

Belén P. Solans and Iñaki F. Trocóniz have received research funding from Boehringer Ingelheim GmbH & Co.KG. Angèle Fleury, Matthias Freiwald, Holger Fritsch an Karin Haug are employed by Boehringer Ingelheim GmbH & Co.KG.

Supplementary material

40262_2017_566_MOESM1_ESM.tif (157 kb)
Supplementary Fig. S1 Schematic of the pharmacokinetic model for volasertib (A) and cytarabine (B). CL total plasma clearance; CL/F apparent total plasma clearance, Q2, Q3 and Q4 inter-compartment clearances, V1 apparent volume of distribution of the central compartment, V2, V3 and V4 apparent volumes of distribution for peripheral compartments 2, 3 and 4 respectively, V/F apparent volume of distribution (TIFF 156 kb)
40262_2017_566_MOESM2_ESM.tiff (1.8 mb)
Supplementary Fig. S2 Goodness-of-fit plots (GOFs) corresponding to the selected population pharmacokinetic model for volasertib. Black lines show the unity line. Solid red lines represent smooth curves through the data. CWRES conditional weighted residuals, Obs observations, WRES weighted residuals (TIFF 1862 kb)
40262_2017_566_MOESM3_ESM.docx (29 kb)
Supplementary material 3 (DOCX 29 kb)


  1. 1.
    Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5(3):E33. doi: 10.3390/jcm5030033.CrossRefPubMedGoogle Scholar
  2. 2.
    Hao Z, Kota V. Volasertib for AML: clinical use and patient consideration. Onco Targets Ther. 2015;8:1761–71.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER cancer statistics review, 1975–2012. National Cancer Institute, Bethesda, MD, USA. Accessed 2 June 2017.
  4. 4.
    Erba HP. Finding the optimal combination therapy for the treatment of newly diagnosed AML in older patients unfit for intensive therapy. Leuk Res. 2015;39(2):183–91.CrossRefPubMedGoogle Scholar
  5. 5.
    Shafer D, Grant S. Update on rational targeted therapy in AML. Blood Rev. 2016;30(4):275–83.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Döner H, Weisdorf D, Bloomfield C. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.CrossRefGoogle Scholar
  7. 7.
    Holtrich U, Wolf G, Bräuninger A, Karn T, Böhme B, Rübsamen-Waigmann H, et al. Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci USA. 1994;91(5):1736–40.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Barr FA, Silljé HHW, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004;5(6):429–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Ikezoe T, Yang J, Nishioka C, Yokoyama A. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia. 2009;23(1):1564–76.CrossRefPubMedGoogle Scholar
  10. 10.
    Brandwein JM. Targeting polo-like kinase 1 in acute myeloid leukemia. Ther Adv Hematol. 2015;6(2):80–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gjertsen BT, Schöffski P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy. Leukemia. 2015;29(1):11–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15(9):3094–102.CrossRefPubMedGoogle Scholar
  13. 13.
    Gorlick R, Kolb EA, Teir S, Maris J, Reynolds P, Kang M, et al. Initial testing (stage 1) of the Polo-Like kinase inhibitor volasertib (BI6727), by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2014;61(1):158–64.CrossRefPubMedGoogle Scholar
  14. 14.
    Rudolph D, Impagnatiello MA, Blaukopf C, Sommer C, Gerlich DW, Roth M, et al. Efficacy and mechanism of action of volasertib, a potent and selective inhibitor of Polo-like kinases, in preclinical models of acute myeloid leukemia. J Pharmacol Exp Ther. 2015;352(3):579–89.CrossRefPubMedGoogle Scholar
  15. 15.
    Nokihara H, Yamada Y, Fujiwara Y, Yamamoto N, Wakui H, Nakamichi S, et al. Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs. 2016;34(1):66–74.CrossRefPubMedGoogle Scholar
  16. 16.
    Döhner H, Lübbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, et al. Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy. Blood. 2014;124(9):1426–34.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2015). Ellicott City: Icon Development Solutions; 2015.Google Scholar
  18. 18.
    Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.CrossRefPubMedGoogle Scholar
  19. 19.
    Ahn J, Karlsson M, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. 2008;35(4):401–21.Google Scholar
  20. 20.
    Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Gerlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686–98.CrossRefPubMedGoogle Scholar
  21. 21.
    Jonsson E, Karlsson MO. Automated covariate model building within NONMEM. Pharm Res. 1998;15:1463–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Lindbom L, Pihlgren P, Jonsson EN. PsN toolkit: a collection of computer intensive statistical methods for nonlinear mixed effect modelling using NONMEM. Comput Methods Programs Biomed. 2005;79:241–57.CrossRefPubMedGoogle Scholar
  23. 23.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. 2011;13(2):143–51.Google Scholar
  24. 24.
    Soto E, Staab A, Tillmann C, Trommeshauser D, Fritsch H, Munzert G, et al. Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the plk-1 inhibitor BI 2536 and its application in clinical development. Curr Microbiol. 2010;61(4):785–95.Google Scholar
  25. 25.
    Robert J, Rigal-Huguet F, Hurteloup P. Comparative pharmacokinetic study of idarubicin and daunorubicin in leukemia patients. Hematol Oncol. 1992;10(2):111–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Krogh-Madsen M, Bender B, Jensen MK, Nielsen OJ, Friberg LE, Honoré PH. Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia. Cancer Chemother Pharmacol. 2012;69(5):1155–63.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and NutritionUniversity of NavarraPamplonaSpain
  2. 2.Navarra Institute for Health Research (IdisNA)University of NavarraPamplonaSpain
  3. 3.Translational Medicine and Clinical PharmacologyBoehringer Ingelheim GmbH & Co. KGBiberach an der RissGermany

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