Infusion Rate Dependent Pharmacokinetics of Bendamustine with Altered Formation of γ-hydroxybendamustine (M3) Metabolite Following 30- and 60-min Infusion of Bendamustine in Rats

Abstract

Bendamustine is an alkylating agent administered as 1 h intravenous infusion in the clinic for the treatment of malignant haematological cancers. The aim of the study was to evaluate the pharmacokinetics of bendamustine and its key cytochrome P 450 (CYP) 1A2 mediated γ-hydroxybendamustine (M3) metabolite after 30- and 60-min intravenous infusion of bendamustine in rats. 2 groups were assigned to receive bendamustine either as 30- or 60-min infusion and doses were normalized to 15 mg/kg for the sake of statistical evaluation. Serial pharmacokinetic samples were collected and were analysed for the circulatory levels of bendamustine and its M3 metabolite. Standard pharmacokinetic parameters were generated for bendamustine and its M3 metabolite. Regardless of the intravenous regimens, C_max coincided with end of infusion for both bendamustine and its M3 metabolite. Immediately after stoppage of infusion, a rapid decline in the plasma levels occurred for both bendamustine and M3 metabolite. The C_max and AUC_0-∞ parameters for bendamustine after 60-min infusion were 1.90 and 1.34-fold higher; while CL was lower by 1.32-fold as compared to the 30-min infusion. In contrast, the C_max and AUC_0-∞ after 30-min infusion for the M3 metabolite was 2.15- and 2.78-fold greater; while CL was 2.32-fold lower when compared to the 60-min infusion. However, T_1/2 and Vz values were similar between the 2 intravenous treatments for bendamustine or the M3 metabolite. The data unequivocally confirmed the existence of differential pharmacokinetics of bendamustine and its M3 metabolite as the function of the duration of intravenous infusion.

Key words

bendamustine - γ-hydroxybendamustine) metabolite - pharmacokinetics - alkylating agent - AUC - intravenous

• References

• 1 Leoni LM, Bailey B, Reifert J et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 2008; 14: 309-317
• 2 Warsch S, Hosein PJ, Maeda LS et al. A retrospective study evaluating the efficacy and safety of bendamustine in the treatment of mantle cell lymphoma. Leuk Lymphoma 2012; 53: 1299-1305
• 3 Friedberg JW, Cohen P, Chen L et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol 2008; 26: 204-210
• 4 Ohmachi K, Ando K, Ogura M et al. Multi center phase II study of bendamustine or relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Cancer Sci 2010; 101: 2059-2064
• 5 Treanda^® (bendamustine hydrochloride), prescribing information. Teva Pharmaceuticals USA Inc.. North Wales, PA: 2015
• 6 Pönisch W, Rozanski M, Goldschmidt H et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a phase I clinical trial. Br J Haematol 2008; 143: 191-200
• 7 Fowler N, Kahl BS, Lee P et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol 2011; 29: 3389-3395
• 8 Knauf WU, Lissichkov T, Aldaoud A et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4378-4384
• 9 Ozegowski W, Krebs D. IMET 3393, γ-[1-methyl-5-bis(β-chloroethyl)-amino-benzimidazolyl-2]-butyric acid hydrochloride, a new cytostatic agent from among the series of benzimidazole mustard compounds. Zbl Pharm 1971; 110: 1013-1019
• 10 Hirschberg E, Gellhorn A, Gump WS. Laboratory evaluation of a new nitrogen mustard, 2-[di-(2-chloroethyl)aminomethyl] benzimidazole, and of other 2-chloroethyl compounds. Cancer Res 1957; 17: 904-910
• 11 Woolley DW. Some biological effects produced by benzimidazole and their reversal by purines. J Biol Chem 1944; 152: 225-232
• 12 Preiss R, Sohr R, Matthias M et al. The pharmacokinetics of bendamustine (Cytostasane) in humans. Pharmazie 1985; 40: 782-784
• 13 Teichert J, Baumann F, Chao Q et al. Characterization of two phase I metabolites of bendamustine in human liver microsomes and in cancer patients treated with bendamustine hydrochloride. Cancer Chemother Pharmacol 2007; 59: 759-770
• 14 Darwish M, Bond M, Hellriegel E et al. Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. Cancer Chemother Pharmacol 2015; 75: 1143-1154
• 15 Chovan JP, Li F, Yu E et al Metabolic profile of [¹⁴C]bendamustine in rat urine and bile: preliminary structural identification of metabolites. Drug Metab Dispos 2007; 35: 1744-1753
• 16 Owen JS, Melhem M, Passarell JA et al. Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkinʼs lymphoma. Cancer Chemother Pharmacol 2010; 66: 1039-1049
• 17 Dubbelman AC, Rosing H, Darwish M et al. Pharmacokinetics and excretion of ¹⁴C-bendamustine in patients with relapsed or refractory malignancy. Drugs R D 2013; 13: 17-28
• 18 Bezek S, Scasnár V, Trnovec T et al. Hepatobiliary elimination of bendamustin (Cytostasan) in rats. Pharmazie 1991; 46: 810-811
• 19 Bezek S, Kukan M, Scasnár V et al. Selective uptake of the anticancer drug bendamustine by liver and kidney tissues following its intravenous administration to mice. Methods Find Exp Clin Pharmacol 1996; 18: 117-122
• 20 Guidance for Industry – Safety Testing of Drug Metabolites, USFDA, Center for Drug Evaluation and Research (CDER), February 2008. http://www.fda.gov/OHRMS/ DOCKETS/98fr/FDA-2008-D-0065-GDL.pdf (last accessed Dec 19, 2015)
• 21 Robison TW, Jacobs A. Metabolites in safety testing. Bioanalysis 2009; 1: 1193-1200