Background Carfilzomib (Kyprolis^®) is a second-generation, selective and irreversible proteasome inhibitor. Profound knowledge about the physicochemical stability is necessary in order to determine the ‘beyond-use-dates’ of the reconstituted and diluted ready-to-administer preparations.

Purpose The stability of Kyprolis^® powder reconstituted with sterile water for injections (2 mg/mL) and further diluted with 5% dextrose solutions stored in plastic syringes (0. 8 mg/mL) and polyolefine (PO) infusion bags (0. 6 mg/mL) should be determined after storage under refrigeration (2°C–8°C) or at room temperature (RT, 25°C) for 28 days.

Materials and Methods The chemical stability was determined with a validated stability-indicating RP-HPLC assay with PDA detection based on the known methods published by Hayes et al.¹ and Garg et al.² The physicochemical stability was determined by measuring pH-values and the visual inspection of colour changes and particulate matter.

Reconstituted Kyprolis^® solutions in original glass vials and ready-to-administer preparations in plastic syringes and PO infusion bags were prepared according to the SmPC. The test solutions stored under refrigeration or at RT were analysed at predetermined intervals over a maximum storage period of 28 days. Samples of the test solutions were injected by an autosampler in triplicate. In parallel, pH-values were determined.

Results In test solutions stored under refrigeration, carfilzomib concentrations decreased <6% of the initial concentrations until the end of the test period independent from the concentration or type of primary container. In reconstituted test solutions stored at RT, carfilzomib concentrations fell below 90% of the initial concentration from day 14 of storage onwards. In all test solutions the pH-values remained unchanged. No particulate matter or colour changes were observed over the test period.

Conclusions Carfilzomib containing parenteral solutions (Kyprolis^®) are stable in glass vials after reconstitution as well as diluted infusion solutions in plastic syringes and PO infusion bags over a period of at least 28 days when stored and light-protected under refrigeration.

References

1. . Hayes ME, et al. Remote loading of sparingly water-soluble drugs into liposomes. US Patent Application Publication 2014.

2. . Garg A, et al. Effect of captisol and pH on the stability of carfilzomib (CFZ ) in drug product under oxidative degradation. Available from http://abstracts.aaps.org/Verify/AAPS2015/PosterSubmissions/W5165.pdf