TY - JOUR
T1 - Systemic Exposure of Rituximab Increased by Ibrutinib
T2 - Pharmacokinetic Results and Modeling Based on the HELIOS Trial
AU - Lavezzi, Silvia Maria
AU - de Jong, Jan
AU - Neyens, Martine
AU - Cramer, Paula
AU - Demirkan, Fatih
AU - Fraser, Graeme
AU - Bartlett, Nancy
AU - Dilhuydy, Marie Sarah
AU - Loscertales, Javier
AU - Avigdor, Abraham
AU - Rule, Simon
AU - Samoilova, Olga
AU - Goy, Andre
AU - Ganguly, Siddhartha
AU - Salman, Mariya
AU - Howes, Angela
AU - Mahler, Michelle
AU - De Nicolao, Giuseppe
AU - Poggesi, Italo
N1 - Funding Information:
Dr. Laurie Orloski (independent medical writer) provided writing assistance and Dr. Namit Ghildyal (Janssen Research & Development, LLC.) provided additional editorial support for this manuscript. JdJ, MN MS, AH, MM, and IP are employees of Janssen Research & Development and hold stocks in the company; PC has received research grants from Hoffman-La Roche, Janssen, GlaxoSmithKline, Novartis, and Gilead and fees from AstraZeneca, Hoffmann La Roche, Janssen, Novartis, Astellas, and Mundipharma; GF has received research grants and fees from Janssen and Celgene and fees from Lundbeck; NB has received research grants from Janssen and Pharmacyclics; M-SD has received fees from Gilead, Janssen, and Roche; JL has received fees from Gilead, Janssen, Roche, and Abbvie; SR has received research grants and fees from Janssen, Roche, and Celgene and fees from Pharmacyclics; AG has received research grants and fees from Janssen, Pharmacyclics, Celgene, and Infinity, fees from Takeda and Acerta, and research grants from Genentech; SG has received research grants from Janssen and fees from Onyx and Seattle Genetics; SML, GDN, FD, AA, and OS have no conflicts of interest to disclose. The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff.
Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - bendamustine
KW - ibrutinib
KW - modeling
KW - pharmacokinetics
KW - rituximab
UR - http://www.scopus.com/inward/record.url?scp=85065129151&partnerID=8YFLogxK
U2 - 10.1007/s11095-019-2605-8
DO - 10.1007/s11095-019-2605-8
M3 - Article
C2 - 31044267
AN - SCOPUS:85065129151
VL - 36
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 7
M1 - 93
ER -