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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
  • 243 Downloads

Abstract

Background

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.

Objectives

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

Methods

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.

Results

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.

Conclusions

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.

Notes

Compliance with Ethical Standards

Funding

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)

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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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