Pharmacokinetic-pharmacodynamic (PK-PD) modeling of leukocyte dynamics and lymph node size in chronic lymphocytic leukaemia patients treated with ibrutinib
Eman I. K. Ibrahim (1), Mats O. Karlsson (1) and Lena E. Friberg (1)
(1) Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Objectives: Chronic lymphocytic leukaemia (CLL) is a type of leukaemia that affects developing B-lymphocytes, with a diverse biological and clinical behavior1. Bruton tyrosine kinase (Btk) plays a crucial role in B cell survival and proliferation upon phosphorylation through B cell receptor (BCR) signaling2. Ibrutinib is an oral, a first-in-class irreversible inhibitor of Btk for treatment of relapsed and refractory CLL2. In a phase 1b–2 study of Ibrutinib1, the observed lymphocyte dynamics were heterogeneous among CLL patients. Additionally, patients with lymphocytosis were associated with longer progression free survival than patients without lymphocytosis at 1-and 2-year time points3. In this work, we aim to build-up a population PK-PD model characterizing mechanistically the relationship between systemic exposure to ibrutinib and leukocyte kinetics as well as the longitudinal sum of the product of perpendicular diameters of lymph node (SPD) measurements in order to identify predictors for outcomes and optimize adherence to therapy.
Methods: Data from a phase 1b–2 study which included 132 patients treated with ibrutinib (420 mg/day, n=94; 840 mg/day, n=38) was used in the analysis. The patients were followed-up for a maximum of 2.4 years (median=1.7 years). The final dataset consisted of 2374 plasma concentrations of ibrutinib, 2434 leukocytes measurements and 507 SPD measurements. The pop PK model developed by Marostica et al4 was applied to derive the individual post hoc estimates of PK parameters and daily AUC0-24 values. The non-linear mixed effect modelling approach was used to quantify the relationship between daily AUC0-24 and leukocyte counts along with SPD dynamics simultaneously, considering the mechanism of action of ibrutinib. Different mechanistic model structures were explored based on a previously published study characterizing patients with persistent lymphocytosis5. The model development and the graphical analysis were performed using nlmixr 1.1.1-9 and xpose.nlmixr 0.1.5 packages in R-studio 3.6.3.
Results: The developed model consisted of eight compartments in total: two compartments for each of phosphorylated Btk (pBtk), lymph node size, CLL cells in tissues and blood mimicking two colonies of CLL cells. The first colony is dependent on BCR signaling for proliferation and survival while the second colony is not dependent on BCR signaling for survival. The pBtk was implemented as a relative quantity in a turnover model with a half-life of 2 days. The production of the pBtk was inhibited using an Emax model as a function of daily AUC0-24 (IC50=232 hr.ng.ml-1). Sequentially, this inhibition resulted in blocking the proliferation of CLL cells in tissues for both colonies in addition to inducing the apoptosis in the tissues with a half-life of 12 days, re-distribution from tissues to blood, and blocking homing from blood to tissues for the first colony cells only. Eventually, the CLL cells will die by neglect in the blood with a half-life of 84 days for the first colony cells and 56 days for the second ones. Also, the resistance to ibrutinib was shown to increase exponentially with time for the first colony only with a half-life of 666 days. The total leukocyte count was calculated as the sum of CLL cells and normal leukocytes in blood. The drug effect and kinetics-related parameters were shared between the leukocytes and SPD models. Additionally, the model described the data adequately as assessed by visual predictive checks using 400 simulated datasets.
Conclusions: The developed mechanistic PK-PD model was capable of describing the individual leukocytes and SPD time-courses well. This model framework will further be extended to describe the time-course of blood pressure. Finally, the predicted time-courses of both leukocytes and SPD will be explored for their ability to predict progression free and overall survival using parametric time-to-event models.
Acknowledgments: This study, carried out under YODA Project #: 2020-4386, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C.
References:
[1] Byrd, J. et al. Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia. n engl j med. (2013). doi:10.1056/NEJMoa1215637
[2] Vela, C. et al. Ibrutinib for treatment of chronic lymphocytic leukemia. AM J HEALTH-SYST PHARM. (2016). doi:10.2146/ajhp140760
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[5] Zhong Y. et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. (2014). doi:DOI: 10.1182/blood-2013-09-527853