Abstract 4921: Population pharmacokinetic modeling of ibrutinib administered in patients with relapsed or refractory B cell malignancies eligible for autologous stem cell transplantation
Authors: Rezai Keyvan , Madar Olivier , Bonnet Christophe , Dupuis Jean , Tilly Hervé , Chapelle Thierry Lamy de la , Gouill Steven Le , Verite Ombeline , Assemat Julie , Bret Fanny , Weill Sophie , Lokiec François , Salles Gilles 
Published: August 2018

Background: Ibrutinib is a first-in-class selective, irreversible small molecule inhibitor of Bruton's tyrosine kinase (BTK). The present study's aim is to assess the feasibility and safety and pharmacokinetics (PK) of escalating doses of ibrutinib combined with rituximab (R), dexamethasone (D), ara-C (HA) and one of two platinum compounds (cisplatinum (P) or oxaliplatinum (Ox)) in patients with relapsed or refractory lymphoma. As part of this, Population PK (POPPK) modeling, PK parameters, and inter-individual and inter-occasion variabilities of oral ibrutinib in the presence of R-DHA(P/Ox) were assessed during the dose escalation part of this clinical trial.

Materials and methods: Dataset was obtained from an open label, multicenter, dose escalation, phase Ib study of ibrutinib in combination with R-DHA (P/Ox) in patients with B-cell malignancies. Patients received three doses (280, 420, 560 mg) of oral ibrutinib once a day D5 to D18. Blood samples were collected during cycles 1 and 2 on D5, Just before ibrutinib intake (T0) and at 1, 2 and 4 hours after ibrutinib intake and on D15 at T0 and 1 hour after ibrutinib intake. Ibrutinib plasma concentrations were measured using validated ultra-performance liquid chromatography with tandem mass spectrometry detection with a concentration range 1-400ng/mL. Analyses and POPPK modeling were performed with the nonlinear mixed effect modeling software program Monolix version 4.3.2. The following parameters were calculated Lagtime (Tlag), absorption constant (Ka); apparent distribution volumes (V1/F, V2); apparent clearances (CL/F, Q).

Results: 24 pts (18 male, 6 female), have validated PK data with 184 plasma concentrations. A 2-compartment model with linear elimination and lag time adequately described the total ibrutinib time-concentration curve. The main PK parameters (RSE%) estimated for ibrutinib were Tlag=0.6 (15), Ka=3.36 (36) h-1, CL/F= 699 (12) L/h, Q=182 (1) L/h, V1/F=5,060 (15) L, and V2=32,100 (49) L. The main covariate effect on ibrutinib CL was related to body weight (BW). The inter-individual and variabilities could be well estimated for CL and V1 and inter-occasion variabilities were well estimated for Tlag and V1.

Conclusions: The POPPK modeling satisfactorily described the plasma ibrutinib time-concentration curves in patients. Our data revealed the effect of BW on ibrutinib PK parameters. A large volume of the deep compartment suggest that ibrutinib has large tissue diffusion. The clinical data describes the toxicity and efficacy. This is an analysis of correlation between the PK and the clinical outcomes.

Citation Format: Keyvan Rezai, Olivier Madar, Christophe Bonnet, Jean Dupuis, Hervé Tilly, Thierry Lamy de la Chapelle, Steven Le Gouill, Ombeline Verite, Julie Assemat, Fanny Bret, Sophie Weill, François Lokiec, Gilles Salles. Population pharmacokinetic modeling of ibrutinib administered in patients with relapsed or refractory B cell malignancies eligible for autologous stem cell transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4921.