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

Silvia Maria Lavezzi, Jan de Jong, Martine Neyens, Paula Cramer, Fatih Demirkan, Graeme Fraser, Nancy Bartlett, Marie Sarah Dilhuydy, Javier Loscertales, Abraham Avigdor, Simon Rule, Olga Samoilova, Andre Goy, Siddhartha Ganguly, Mariya Salman, Angela Howes, Michelle Mahler, Giuseppe De Nicolao, Italo Poggesi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number93
JournalPharmaceutical Research
Volume36
Issue number7
DOIs
StatePublished - 1 Jul 2019

Keywords

  • bendamustine
  • ibrutinib
  • modeling
  • pharmacokinetics
  • rituximab

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