Belén P Solans1,2, Angèle Fleury3, Matthias Freiwald3, Holger Fritsch3, Karin Haug3, Iñaki F Trocóniz4,5. 1. Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain. 2. Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain. 3. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany. 4. Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, 31008, Pamplona, Spain. itroconiz@unav.es. 5. Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain. itroconiz@unav.es.
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 receivingcytarabine 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 withcytarabine 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.
RCT Entities:
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.
Authors: T Ikezoe; J Yang; C Nishioka; Y Takezaki; T Tasaka; K Togitani; H P Koeffler; A Yokoyama Journal: Leukemia Date: 2009-05-07 Impact factor: 11.528
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Authors: Klaus H Metzeler; Tobias Herold; Maja Rothenberg-Thurley; Susanne Amler; Maria C Sauerland; Dennis Görlich; Stephanie Schneider; Nikola P Konstandin; Annika Dufour; Kathrin Bräundl; Bianka Ksienzyk; Evelyn Zellmeier; Luise Hartmann; Philipp A Greif; Michael Fiegl; Marion Subklewe; Stefan K Bohlander; Utz Krug; Andreas Faldum; Wolfgang E Berdel; Bernhard Wörmann; Thomas Büchner; Wolfgang Hiddemann; Jan Braess; Karsten Spiekermann Journal: Blood Date: 2016-06-10 Impact factor: 22.113