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

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  • 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 .


  • 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

publication date

  • July 2019