Population Pharmacokinetic Model of Ibrutinib, a BTK Inhibitor for the Treatment of B-cell malignancies

Objectives: Ibrutinib (PCI-32765) is an oral Bruton’s tyrosine kinase (BTK) inhibitor currently under development for the treatment of B-cell malignancies. Here we evaluated a population pharmacokinetic model for describing the pharmacokinetic data collected to date in clinical trials with ibrutinib. Methods: Preliminary ibrutinib plasma data were available from 3 clinical studies: i) a phase 1 dose-escalation study, in recurrent B-cell malignancies (doses of 1.25-12.5 mg/kg and fixed doses of 560 mg); ii) a phase 1b/2 dose-finding study in chronic lymphocytic leukemia (doses of 420 and 840 mg); iii) an open-label phase 2 fixed-dose study, in mantle cell lymphoma (dose level of 560 mg). Overall, approximately 2700 observations were collected in 197 subjects following single and repeated daily dosing, at different days of the treatment cycles. A 2-compartment model with sequential zero-first order absorption and elimination was implemented. Analyses were performed by adopting a log transform-both-sides approach and an additive error model. Inter-individual variability was implemented using an exponential model. The first-order conditional estimation method was implemented using NONMEM v 7.1. Results: A linear model, constructed with data collected following single and repeated doses of ibrutinib at different dose levels, demonstrated that the compound pharmacokinetics were dose- and time-independent. Ibrutinib was rapidly absorbed and was characterized by a high oral plasma clearance (approximately 1000 L/h) and a high apparent volume of distribution at steady-state (approximately 10,000 L). Although both values are confounded by absolute bioavailability, these values suggest that ibrutinib clearance and volume are high. The half-lives of the distribution and terminal phases were estimated to be less than one hour and approximately 16 hours, respectively. Pharmacokinetic parameters were not found to be significantly different between dose levels, studies, and clinical indications. Population parameters and their inter-individual variability were estimated with good precision. The model proved to be satisfactory in terms of goodness-of-fit, individual fittings, and visual predictive checks. Conclusions: The proposed population pharmacokinetic model was able to describe the plasma concentration-time profiles of ibrutinib from trials in different indications well.