An evaluation of the potential for drug–drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma

Mona Darwish,Luann Phillips,Mary Bond,Elizabeth Ludwig,Philmore Robertson,John M Burke,Mihaela C Munteanu,Edward Hellriegel

doi:10.1007/s00280-014-2445-5

Abstract

PurposeBendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug–drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma.MethodsData were derived from a bendamustine–rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration–time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy.ResultsThe established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration–time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate.ConclusionsNeither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

Highlights

Bendamustine is a novel alkylating agent indicated for the treatment of chronic lymphocytic leukemia (CLL) and Cancer Chemother Pharmacol (2014) 73:1119–1127 indolent B cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen [1,2,3,4]
Rituximab concentrations observed in the presence of bendamustine at 24 h and 7 days post-end of rituximab infusion (EOI) were lower than those reported in the literature
Rituximab concentrations in the presence and absence of bendamustine in the current analysis were found to be consistently lower than those reported in the literature, with a similar difference in concentration at EOI of rituximab and 24 h post-infusion, and a larger difference in concentration at 7 days post-infusion; all of the disparities could potentially be due to differences in the duration of the rituximab infusion or assay methodology/sensitivity

Summary

Introduction

Bendamustine is a novel alkylating agent indicated for the treatment of chronic lymphocytic leukemia (CLL) and Cancer Chemother Pharmacol (2014) 73:1119–1127 indolent B cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen [1,2,3,4]. A chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen, is indicated for the treatment of CLL and NHL [5,6,7,8] Small molecule drugs, such as bendamustine, are increasingly being used in combination with biologics to treat various diseases [9,10,11,12], and such combinations may be especially beneficial in patients with lymphoid malignancies [13]. Rituximab binds to the CD20 antigen, a hydrophobic transmembrane protein [8], and is metabolized to peptides and amino acids that can be recycled in the body or excreted in the urine [19] Oxidative metabolizing enzymes, such as CYPs, are not believed to be involved in rituximab elimination [20]

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Conclusion