Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial

• Published in: Pharmaceutical research 2019-07, Vol.36 (7), p.93-12, Article 93
• Main Authors: Lavezzi, Silvia Maria, de Jong, Jan, Neyens, Martine, Cramer, Paula, Demirkan, Fatih, Fraser, Graeme, Bartlett, Nancy, Dilhuydy, Marie-Sarah, Loscertales, Javier, Avigdor, Abraham, Rule, Simon, Samoilova, Olga, Goy, Andre, Ganguly, Siddhartha, Salman, Mariya, Howes, Angela, Mahler, Michelle, De Nicolao, Giuseppe, Poggesi, Italo
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bendamustine Hydrochloride - adverse effects; Bendamustine Hydrochloride - pharmacokinetics; Bendamustine Hydrochloride - therapeutic use; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chronic lymphocytic leukemia; Exposure; Female; Humans; Immunotherapy; Inhibitor drugs; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphatic leukemia; Lymphoma; Male; Medical Law; Middle Aged; Models, Biological; Monoclonal antibodies; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Pyrazoles - metabolism; Pyrimidines - metabolism; Research Paper; Rituximab; Rituximab - pharmacokinetics; Targeted cancer therapy; Treatment Outcome
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-019-2605-8

Introduction In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. Methods 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. Results Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. Conclusions BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. Trial Registration This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .