Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites

Abstract

Purpose: Bendamustine 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.

Methods: A 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.

Results: Bendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (~40 min) as the effective t 1/2 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/m(2) 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.

Conclusions: Altogether, the findings support dosing based on body surface area for most patient populations.

Fig. 1

Bendamustine and its main metabolites. Reproduced with permission of ASPET [23]

Fig. 2

Effect of body surface area on systemic exposure. a The line represents a linear regression. b Boxes are 25th, 50th, and 75th percentiles; whiskers are 5th and 95th percentiles. The numbers above the box represent the number of patients. Pediatrics panel: adapted with permission of Informa Healthcare [27]

Fig. 3

Effect of age on systemic exposure. Boxes are 25th, 50th, and 75th percentiles; whiskers are 5th and 95th percentiles. Asterisks are data points outside this range. The numbers above the box represent the number of patients. Pediatrics panel: adapted with permission of Informa Healthcare [27]

Fig. 4

Effect of hepatic impairment on systemic exposure. Boxes are 25th, 50th, and 75th percentiles; whiskers are 5th and 95th percentiles. Asterisks are data points outside this range. The numbers above the box represent the number of patients. Pediatrics panel: adapted with permission of Informa Healthcare [27]

Fig. 5

Effect of renal impairment on systemic exposure. Boxes are 25th, 50th, and 75th percentiles; whiskers are 5th and 95th percentiles. Asterisks are data points outside this range. Triangles show individual data points for patients with mild renal dysfunction. The numbers above the box represent the number of patients. Pediatrics panel: adapted with permission of Informa Healthcare [27]

Fig. 6

Pharmacokinetics in presence or absence of CYP1A2 inhibitors/inducers. Boxes are 25th, 50th, and 75th percentiles; whiskers are 5th and 95th percentiles. The numbers above the box represent the number of patients. Adapted with permission of Informa Healthcare [27]

Fig. 7

Kaplan–Meier plot of PFS, stratified by median bendamustine AUC. With kind permission from Springer Science+Business Media: Figure 5 [17]