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 the product of perpendicular diameters [SPD] of lymph nodes) and hypertension toxicity (i.e., blood pressure), and their association with overall survival is needed. Here, we present a semi-mechanistic pharmacokinetic-pharmacodynamic modeling framework to characterize such relationships and facilitate dose optimization. Data from a phase Ib/II study were used, including ibrutinib plasma concentrations to derive daily 0-24-h area under the concentration-time curve, leukocyte count, SPD, survival, and blood pressure measurements. A nonlinear mixed effects modeling 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 dropout 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 approximate to 97%); the latter had, on average, approximate to 20% lower proportions of patients with hypertension. The developed modeling framework offers an improved understanding of the relationships among ibrutinib exposure, efficacy and toxicity biomarkers. This framework can serve as a platform to assess dosing schedules in a biologically plausible manner. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Ibrutinib is efficacious against various B-cell malignancies, but has been linked to dose-limiting hypertension on long-term therapy. Retrospective analyses have suggested that dose reductions may improve the management of adverse events without compromising the outcomes. WHAT QUESTION DID THIS STUDY ADDRESS? Does a stepwise reduction protocol for ibrutinib dosing reduce hypertension development without affecting the efficacy? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? A population semi-mechanistic pharmacokinetic-pharmacodynamic modeling framework was developed to characterize relationships between systemic ibrutinib exposure, leukocyte count, lymph node size, and hypertension in patients with chronic lymphocytic leukemia. The simulated cell count profiles revealed that the approved dosing schedule resulted in the highest reduction in tumor burden, whereas the de-escalation schedules had approximate to 20% lower proportions of simulated patients with hypertension than the approved schedule. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? The developed semi-mechanistic framework possesses biological features that enable reliable predictions of biomarkers. Thus, this framework can be used as a time-and resource-saving tool for evaluating different dosing schedules before being tested in clinical trials.

Automated summary

This study developed a semi-mechanistic pharmacokinetic-pharmacodynamic modeling framework to investigate the relationship between systemic exposure to ibrutinib and its efficacy and toxicity biomarkers. The simulations showed that lower dosing schedules can reduce the incidence of hypertension without compromising the reduction in tumor burden compared to the approved dosing schedule.