Abstract 4634: Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies
Authors: Marostica Eleonora , Sukbuntherng Juthamas , Loury David , Jong Jan D. , Trixhie Xavier Woot de , Vermeulen An , Nicolao Giuseppe de , O'Brien Susan , Byrd John C. , Advani Ranjana , McGreivy Jesse , Poggesi Italo 
Published: May 2015

Abstract
Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are B-cell malignancies with initial high response rate to chemoimmunotherapy, but are largely considered incurable. Ibrutinib (PCI-32765), an oral Bruton's tyrosine kinase inhibitor recently approved to treat MCL, is under development for other B-cell malignancies. We developed a population pharmacokinetic (PK) model for describing data collected to date in clinical trials with ibrutinib.
Ibrutinib plasma data were available from 3 clinical trials: 1) a phase 1 dose-escalation study in recurrent B-cell malignancies (doses: 1.25-12.5 mg/kg and 560 mg fixed); 2) a phase 1b/2 dose-finding study in CLL (doses: 420 and 840 mg); 3) an open-label, phase 2, fixed-dose study in MCL (dose: 560 mg). Overall, ≈3477 observations were collected in 245 patients following single and repeated daily dosing on different treatment days. A 2-compartment model with sequential zero to first order absorption and first order elimination was implemented. Analyses were performed with a log-transform-both-sides approach. Additive and exponential models were used to describe residual and inter-individual variability, respectively. The first-order conditional estimation method was implemented using NONMEM v 7.1.
A linear model constructed with data collected following single and repeated doses of ibrutinib at different dose levels demonstrated that the PK was dose and time independent. Ibrutinib was rapidly absorbed and was characterized by a high oral plasma clearance (≈1000 L/h with between-subject variability of 21.9%; this, for a dose of 560 mg, would lead to an average steady state concentration of ≈22 ng/mL, ie, ≈50 nM) and a high apparent volume of distribution at steady state (≈10,000 L). Though both values are confounded by absolute bioavailability, these values suggest that ibrutinib clearance and volume are high. The half-lives of distribution and terminal phases were estimated to be &lt;1 h and ≈14 h, respectively. Administration of ibrutinib in fasting state was characterized by a 67% relative bioavailability compared to both meal conditions used in the clinical trials and administration after a high-fat meal. The PK parameters were not found to be significantly different between studies and clinical indications. Body weight and coadministration of antacids had a marginal effect on volume of distribution and duration of absorption processes, respectively. No significant effect of covariates such as age, gender, patient pretreatment, or clinical chemistry data was found. Population parameters and inter-individual variability were estimated with good precision. The model provided satisfactory goodness of fit, individual fittings, and visual predictive checks.
In conclusion, the proposed population PK model was able to accommodate the plasma concentration-time profiles of ibrutinib across various trials.
Citation Format: Eleonora Marostica, Juthamas Sukbuntherng, David Loury, Jan De Jong, Xavier Woot de Trixhie, An Vermeulen, Giuseppe de Nicolao, Susan O'Brien, John C. Byrd, Ranjana Advani, Jesse McGreivy, Italo Poggesi. Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4634. doi:10.1158/1538-7445.AM2014-4634