Abstract
e18522 Background: The PK profile of bendamustine as a monotherapy in adult patients is well described. Because pathways of small molecules and monoclonal antibodies are distinct, a direct drug interaction between bendamustine and rituximab was not expected. Methods: In order to confirm the lack of a PK interaction, the population PK model that was developed based on the bendamustine monotherapy (120 mg/m2) was evaluated to determine its applicability to combination therapy (rituximab 375 mg/m2 on day 1, bendamustine 90 mg/m2 on days 1 and 2) in patients with NHL and MCL. Once the applicability was confirmed, model-predicted Bayesian bendamustine clearance (CL) values for monotherapy and combination therapy were generated and compared using the Wilcoxon signed rank test on the log-transformed CL values (alpha=0.05). Results: The previously developed population PK model in patients receiving bendamustine monotherapy was used to generate 500 sets of single-agent bendamustine concentrations at the same sampling times and bendamustine dosing regimens as those observed in the combination-with-rituximab study. Median, 10th, and 90th percentiles of observed bendamustine concentrations following combination therapy and modeled bendamustine concentrations following monotherapy exhibited similar patterns. Although slightly greater than 10% of the observed data fall above (13%) or below (15%) the specific percentiles, the previously developed monotherapy population PK model was considered applicable to the data following combination therapy. The 25th to 75th percentiles of the bendamustine CL estimates were similar for combination and monotherapy with median values within 8% of each other. The 2-sided Wilcoxon signed rank test of the log-transformed CL values did not show a statistical difference between the 2 groups (p >0.61). Conclusions: Comparison of bendamustine plasma concentrations and CL estimates in patients receiving bendamustine in combination with rituximab to those in patients receiving bendamustine alone indicate that rituximab does not affect systemic exposure to bendamustine. Support: Teva Pharmaceutical Industries Ltd.
Published Version
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