Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin's lymphoma

Abstract

Purpose: The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety.

Methods: Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined.

Results: Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics.

Conclusions: The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.

Fig. 1

Schematics of the Bendamustine, M4, and M3 Final Pharmacokinetic Models

Fig. 2

Measured Plasma Bendamustine Concentration Versus Time Since Last Dose With the Bendamustine Model Typical Value Population-Predicted Profile Overlaid

Fig. 3

Percentiles of Simulated Data From the Visual Predictive Check of the Final Bendamustine Pharmacokinetic Model Overlaid on the Observed Concentration Data

Fig. 4

Measured Plasma M3 (upper panel) and M4 (lower panel) Concentration Versus Time Since Last Dose With the Model Typical Value Population-Predicted Profiles Overlaid

Fig. 5

Kaplan-Meier Plot of Progression-Free Survival, Stratified by Median Cycle 1 Bendamustine AUC

Fig. 6

Observed and Model-Predicted Probabilities of Adverse Events: Occurrence of Nausea Versus Bendamustine C_max (upper panel) and Occurrence of Vomiting Versus the Number of Prior Treatment Courses (lower panel)