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 - 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
SN - 0724-8741
VL - 36
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 7
M1 - 93
ER -