Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Abstract

PurposeBendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin’s lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug–drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies.MethodsA literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion.ResultsBendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t1/2 (~40 min) as the effective t1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug–drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m2 is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure–efficacy response relationship has been observed.ConclusionsAltogether, the findings support dosing based on body surface area for most patient populations.

Safety and Pharmacokinetics of Bendamustine Rapid‐Infusion Formulation

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