Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic‐pharmacodynamic models

Abstract

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 ≈ 97%); the latter had, on average, ≈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.

Pressure Sensors: Working Principles of Static and Dynamic Calibration

“…Dynamic pressure measurements are also required in industrial deaerators that are used to remove dissolved gases, such as oxygen, nitrogen and carbon dioxide, from water to minimize corrosion risks [ 3 ]. On the other hand, in other application areas, such as military engineering, chemical explosion tests [ 4 ], petroleum exploration and well testing [ 5 ], gas turbine testing and combustion engine testing [ 6 , 7 ], and biomedical applications [ 8 ], among others, dynamic calibration of pressure sensors is essential. A typical example that can be referred to in the automotive area is related to air flow control in combustion engines [ 9 ].…”