Lavezzi, Silvia Maria, de Jong, Jan, Neyens, Martine, Cramer, Paula, Demirkan, Fatih ORCID: 0000-0002-1172-8668, Fraser, Graeme, Bartlett, Nancy ORCID: 0000-0001-8470-394X, Dilhuydy, Marie-Sarah, Loscertales, Javier, Avigdor, Abraham, Rule, Simon, Samoilova, Olga, Goy, Andre ORCID: 0000-0001-5125-6522, Ganguly, Siddhartha, Salman, Mariya, Howes, Angela, Mahler, Michelle, De Nicolao, Giuseppe and Poggesi, Italo (2019). Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Pharm. Res., 36 (7). NEW YORK: SPRINGER/PLENUM PUBLISHERS. ISSN 1573-904X

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lavezzi, Silvia MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neyens, MartineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cramer, PaulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demirkan, FatihUNSPECIFIEDorcid.org/0000-0002-1172-8668UNSPECIFIED
Fraser, GraemeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartlett, NancyUNSPECIFIEDorcid.org/0000-0001-8470-394XUNSPECIFIED
Dilhuydy, Marie-SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loscertales, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avigdor, AbrahamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rule, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samoilova, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goy, AndreUNSPECIFIEDorcid.org/0000-0001-5125-6522UNSPECIFIED
Ganguly, SiddharthaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salman, MariyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howes, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahler, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Nicolao, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poggesi, ItaloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-137286
DOI: 10.1007/s11095-019-2605-8
Journal or Publication Title: Pharm. Res.
Volume: 36
Number: 7
Date: 2019
Publisher: SPRINGER/PLENUM PUBLISHERS
Place of Publication: NEW YORK
ISSN: 1573-904X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTICENTER PHASE-II; TARGET; BENDAMUSTINE; ASSOCIATION; ELIMINATION; CLEARANCE; BTKMultiple languages
Chemistry, Multidisciplinary; Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13728

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