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

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.

Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

“…Two recent studies and data from the literature indicate that the potential for a drug–drug interaction between bendamustine and rituximab is low [ 52 ]. One of the studies was an open-label, multicenter, phase 3 study in adults who received bendamustine–rituximab combination therapy for advanced indolent NHL or mantle cell lymphoma [ 52 ].…”

“…Two recent studies and data from the literature indicate that the potential for a drug–drug interaction between bendamustine and rituximab is low [ 52 ]. One of the studies was an open-label, multicenter, phase 3 study in adults who received bendamustine–rituximab combination therapy for advanced indolent NHL or mantle cell lymphoma [ 52 ]. The other study, which served as the data source for the bendamustine population pharmacokinetic model used in the combination therapy study, was the aforementioned phase 3 NHL study in adults who received bendamustine monotherapy [ 17 ].…”

“…In the bendamustine–rituximab combination therapy study, patients received rituximab (375 mg/m 2 ) followed by bendamustine (90 mg/m 2 ) on day 1 of each cycle and bendamustine (90 mg/m 2 ) on day 2 of each cycle. The final analysis dataset included bendamustine concentration samples from 49 patients and rituximab concentration samples from 19 patients [ 52 ].…”

“…In the bendamustine monotherapy study, patients received bendamustine (120 mg/m 2 ) on days 1 and 2 of each cycle. Bendamustine plasma concentrations from 78 adult patients were described in a three-compartment, open population pharmacokinetic model with zero-order input and first-order elimination [ 17 , 52 ].…”

Commonality of rituximab pharmacokinetic disposition in nephrotic syndrome and autoimmune cytopenias in chronic lymphocytic leukemia patients

“…In a recent publication, the patient-and cancer type-based disposition of rituximab has been elegantly collated by Darwish et al, in comparing a pharmacokinetic interaction of bendamustine with rituximab [3]. Across several stratifications, comprising patient cohorts such as non-Hodgkin lymphoma (NHL) with low tumor burden, autoimmune disorders, advanced follicular lymphoma, recurrent low-grade or follicular NHL and amyloid light-chain amyloidosis, the concentrations of rituximab were found to be highly variable on the day of infusion and both in subsequent distributive and elimination phases of rituximab [3].…”