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 (NHL), and supported understanding of exposure-response relationships for efficacy and safety. Methods Bendamustine was administered as a 60-minute 120 mg/m2 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 t1/2 (40 minutes) was considered the pharmacologically relevant (beta elimination) t1/2 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/m2 administration, except bendamustine Cmax 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 t1/2 and low concentrations of bendamustine observed by 12 hours 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 Cmax increases.

A Canadian Perspective on the Safe Administration of Bendamustine and the Prevention and Management of Adverse Events

“…Our experience with bendamustine indicates that a reduced infusion time of 30 minutes seems to increase the associated infusion-related reactions (irrs), especially delayed irrs occurring 4-6 hours after infusion. Recent work by Owen et al is consistent with that experience, showing a higher probability of nausea occurring at peak plasma concentration of the drug 16 . Short bendamustine infusions (30 minutes) might potentially be increasing the peak plasma concentration, which would explain those observations.…”

“…Bendamustine is metabolized primarily by hydrolysis to form inactive metabolites 16 . A secondary metabolic route through the enzyme cytochrome P450 1A2 (CYP1A2) produces two active but minor metabolites 1 .…”

The expanding role of bendamustine in chronic lymphocytic leukemia

“…14 Bendamustine can be safely administered to patients with mild-to-moderate renal failure without significantly changing the degree of systemic exposure. 15 Although it is not approved in patients with a creatinine clearance (CrCl) ,40 mL/min, case reports have indicated tolerability in those undergoing hemodialysis. 16,17 Similarly, it can be administered to patients with mild hepatic impairment, defined as an elevated total bilirubin of 1-1.5 times the upper limit of normal or aspartate aminotransferase (AST) of 1-2.5 times the upper limit of normal.…”

The role of bendamustine in the treatment of indolent non-Hodgkin lymphoma

“…33 Following a 60-minute intravenous administration in patients with NHL, serum bendamustine declined in a rapid biphasic manner (t½α = 17 minutes, t½β = 42 minutes) and a slow terminal phase (t½c = 110 hours), but the terminal phase composed less than 1% of the total AUC, and therefore, the half-life of the β-phase represents bendamustine mean half-life, which is approximately 40 minutes. 34 The drug is eliminated mainly via feces and to a lesser extent in the urine. A preclinical study illustrated that approximately 90% of administered bendamustine was recovered in feces.30 Bendamustine is highly bound to serum protein (95%), primarily to albumin.…”

“…34 Nevertheless, bendamustine should be used with caution in patients with mild hepatic dysfunction and mild to moderate renal impairment, bendamustine should be avoided with more profound failure (CrCL  40 mL/min, AST or ALT  2.5 upper limit of normal (ULN), or total bilirubin 1.3 ULN) as limited studies have been executed in these sittings. 30 Drug-drug interactions with bendamustine have not been well-studied, but due to the role hepatic cytochrome P450 1A2 enzyme plays in bendamustine biotransformation, 33 CYP P450 1A2 inhibitors as well as inducers may lead to altered serum levels, and dosage adjustment of bendamustine may be needed in these situations.…”