Fanny Gallais (1), Loïc Ysebaert (2), Fabien Despas (3), Sandra De Barros (4), Loïc Dupré (5), Anne Quillet-Mary (1), Fabienne Thomas (1,6), Lucie Obéric (2), Ben Allal (1,6), Etienne Chatelut (1,6), Mélanie White-Koning (1)
(1) Cancer Research Center of Toulouse, Inserm U1037, Université Paul Sabatier, Toulouse, France, (2) Department of Hematology, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France, (3) Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance, Pharmacoepidemiology and Drug Information, INSERM UMR 1027 Pharmacoepidemiology, Assessment of Drug Utilization and Drug Safety, CIC 1426, Toulouse University Hospital, Faculty of Medicine, Toulouse, France, (4) Department of Clinical Pharmacology, Toulouse University Hospital, Toulouse, France, (5) Center for Pathophysiology of Toulouse Purpan, INSERM UMR1043 & CNRS UMR5282, Paul Sabatier University, Toulouse, France, (6) Laboratory of Pharmacology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse -Oncopole, Toulouse, France
Objectives: Ibrutinib is a targeted therapy used for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. CLL is the most frequent leukemia in adults in the Western world. It is characterized by the accumulation of non-functional B-cells in bone marrow, lymphoid tissues and blood. Ibrutinib blocks the B-cell receptor signalling pathway by inhibiting the Bruton Tyrosine kinase which has several effects on the CLL cells: anti-proliferation, egress from lymph nodes, inhibition of re-homing to niches and death in blood and niches. Circulating lymphocyte count over time is an important clinical indicator in CLL. Three types of response are observed in patients treated with ibrutinib: inexistent, transitory and prolonged lymphocytosis [1]. A study has shown that the last group had better long-term prognosis [2]. The objective of this work was to develop a population model describing circulating lymphocyte dynamics under ibrutinib treatment and to assess the influence of pharmacokinetics (PK) on pharmacodynamics (PD).
Methods: The “PKE3I” study was initiated in 2016 at IUCT-Oncopole hospital. Patients treated with ibrutinib for CLL, mantle cell lymphoma or Waldenstrom macroglobulinemia were included in the study and followed-up for two years. PK blood sampling was performed and lymphocyte count was assessed at several hospital visits. Additionally, lymphocyte count observations before the initiation of the first line of treatment were obtained from routine visits for patients with CLL subsequently included or not in PKE3i. First, a population PD model was developed to describe the lymphocyte count dynamics under ibrutinib treatment. Then ibrutinib concentrations and a previously developed population PK model [3] were used to assess the PK-PD relationship. The models were developed in Nonmem 7.4.
Results: A total of 77 CLL patients and 506 lymphocyte counts under ibrutinib treatment were available in the PKE3i study. The number of patients with inexistent, transitory and prolonged lymphocytosis was 31, 21 and 25 respectively. The final PD model describing lymphocyte count dynamics was composed of two compartments: one for lymph nodes and one for blood circulation. Lymphocytes proliferate in lymph nodes (K_prol), are released in blood circulation (K_out) where they die (K_death). Additional lymphocyte count observations before the beginning of ibrutinib treatment were available for 14 PKE3i patients. Moreover, routine data from 17 additional patients with CLL before their first line of treatment were available. All observations were included in the PK-PD analysis. The preliminary PK-PD model has the same structure as the PD model with two additional features: logistic growth to describe increasing lymphocyte counts before the initiation of ibrutinib (K_log), and homing of lymphocytes from blood to lymph nodes (K_hom). The model includes linear drug effects on K_out (Slope_out=0.177) and K_hom (Slope_hom=0.444). So far, PK was included in the model as the individual mean ibrutinib concentration for each patient. The next step will be to build a full PK-PD model using a previously developed PK model for ibrutinib.
Conclusions: The first nonlinear mixed-effects PD model describing lymphocyte dynamics under ibrutinib treatment was developed. The final model fits the observed data well for all types of profiles. A preliminary PK-PD model was obtained and the influence of PK on PD response will be further investigated. Covariate analysis will be performed and the relationship between PD response and clinical outcome will be assessed.
References:
[1] Herman SEM, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. nov 2014;28(11):2188‑96.
[2] Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre SE, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83‑91.
[3] Gallais F et al. Population pharmacokinetics of ibrutinib and its dihydrodiol metabolite in patients with lymphoid malignancies. Poster PAGE 2019.
Reference: PAGE () Abstr 9382 [www.page-meeting.org/?abstract=9382]
Poster: Drug/Disease Modelling - Oncology