Assessment of Ibrutinib Scheduling on Leukocyte, Lymph Node Size and Blood Pressure Dynamics in Chronic Lymphocytic Leukemia through Pharmacokinetic-Pharmacodynamic Models.

Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor for treating chronic lymphocytic leukemia (CLL). It has also been associated with hypertension. The optimal dosing schedule for mitigating this adverse effect is currently under discussion. A quantification of relationships between systemic ibrutinib exposure and efficacy (i.e., leukocyte count and sum of product of perpendicular diameters of lymph nodes (SPD)) and hypertension toxicity (i.e., blood pressure), and their association with overall survival is needed. Here, we present a semi-mechanistic pharmacokinetic (PK)-pharmacodynamic (PD) modelling framework to characterize such relationships and facilitate dose optimization. Data from a phase 1b/2 study were used, including ibrutinib plasma concentrations to derive daily AUC , leukocyte count, SPD, survival and blood pressure measurements. A non-linear mixed effects modelling approach was applied, considering ibrutinib's pharmacological action and CLL cell dynamics. The final framework included (i) an integrated model for SPD and leukocytes consisting of four CLL cell subpopulations with ibrutinib inhibiting phosphorylated Btk production, (ii) a turnover model in which ibrutinib stimulates an increase in blood pressure, and (iii) a competing risk model for drop-out and death. Simulations predicted that the approved dosing schedule had a slightly higher efficacy (24-month, progression free survival (PFS) 98%) than de-escalation schedules (24-month, average PFS ≈97%); the latter had, on average, ≈20% lower proportions of patients with hypertension. The developed modelling framework offers an improved understanding of the relationships between ibrutinib exposure, efficacy and toxicity biomarkers. This framework can serve as a platform to assess dosing schedules in a biologically plausible manner.