Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies
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Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.
Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25–12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.
A two-compartment PK model with sequential zero–first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.
The proposed population PK model was able to describe the plasma concentration–time profiles of ibrutinib across various trials. The linear model indicated that the compound’s PK was dose independent and time independent.
KeywordsPhase I–II ADME Nonlinear mixed effects model Covariate analysis
The authors thank Purvi Jejurkar (Pharmacyclics) for bioanalytical support and Rishabh Pandey (SIRO Clinpharm Pvt. Ltd.) for additional editorial assistance. The authors also thank the study participants, without whom this study would not have been accomplished. The authors received financial support from Janssen Research and Development and Pharmacyclics.
Conflict of interest
Juthamas Sukbuntherng, David Loury, and Jesse McGreivy are employees of Pharmacyclics; Jan de Jong, Xavier Woot de Trixhe, An Vermeulen, and Italo Poggesi are employees of Janssen R&D.
- 7.Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al (2010) The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 107:13075–13080PubMedCentralPubMedCrossRefGoogle Scholar
- 8.Poggesi I, Sardu ML, Marostica E, Sukbuntherng J, Chang BY, de Jong J, Woot de Trixhe X, Vermeulen A, De Nicolao G, O’Brien SM, Byrd JC, Advani RH, James DF, Deraedt W, Beaupre D, Wang M (2014). Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-Cell malignancies. Accepted for AACR meeting “Hematological malignancies: Translating discoveries in novel therapies” September 20–23, 2014 Sheraton Philadelphia Downtown Philadelphia, PA, USAGoogle Scholar
- 9.Beal S, Sheiner LB, Boeckmann A, Bauer RJ, NONMEM (2009) User’s guides. Icon Development Solutions, Ellicott CityGoogle Scholar
- 15.R Development Core Team (2012) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, (URL http://www.R-project.org)
- 16.DIDB: drug interaction DataBase: University of Washington (www.druginteractioninfo.org), Accessed 20 March 2013
- 19.Jong de J, Sukbuntherng J, Skee D, Murphy J, O’Brien S, Byrd JC, et al (2014) Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. AACR annual meeting. Abstract #4637: April 5–9Google Scholar
- 20.Imbruvica prescribing information (2013) http://www.imbruvica.com/downloads/Prescribing_Information.pdf. Accessed 24 February 2013
- 21.Sukbuntherng J, Jong de J, Skee D, Pak Y, Fardis M, O’Brien S et al (2014) Pharmacokinetics and safety of ibrutinib with concomitant use of CYP3A inhibitors in patients with B-cell malignancies. ACCP annual meetingGoogle Scholar
- 23.Montgomery DC, Peck EA (1982) Introduction to linear regression analysis. Wiley, London, p 277Google Scholar