Optimizing Ibrutinib Posology in Chronic Lymphocytic Leukemia Using a Semi‐Mechanistic Pharmacometric Framework

Ibrutinib, a Bruton's tyrosine kinase (Btk) inhibitor, is a key therapy for chronic lymphocytic leukemia (CLL). In clinical practice, adverse events, such as hypertension, frequently necessitate dose reductions or treatment discontinuation. Emerging evidence suggests that reduced doses may retain clinical efficacy while mitigating toxicity. The synergistic ibrutinib-venetoclax combination remains understudied at low doses, particularly for ibrutinib. This study aimed to explore dose optimization strategies, with/without venetoclax, in treatment-naïve (TN) and relapsed/refractory (R/R) CLL using mechanism-based, model-informed approaches to characterize the relationship between systemic ibrutinib exposure and efficacy and safety biomarkers. We leveraged data from phase 1b/2 and 3 studies, including plasma concentrations, leukocyte and lymphocyte counts, lymph node and spleen size measurements, and blood pressure. A previously developed semi-mechanistic population pharmacokinetic-pharmacodynamic (PKPD) framework was re-evaluated, extended by integrating additional biomarkers and identifying differences between TN and R/R patients, and used to simulate alternative dosing strategies. The model successfully captured the temporal dynamics of all biomarkers simultaneously. We quantified a 76% longer phospho-Btk half-life and a 43% shorter peripheral CLL cell half-life in TN versus R/R patients, with no evidence of ibrutinib resistance in TN patients. Dose reductions based on response depth or toxicity preserved comparable response rates and progression-free survival to standard dosing. Ibrutinib de-escalation schedules with venetoclax resulted in a ≤ 5% reduction in peripheral blood measurable residual disease compared to standard dosing at 2 years. This PKPD framework supports dose individualization to improve tolerability without sacrificing treatment outcomes, offering a path toward more personalized, effective CLL management.