Physicochemical stability of CPX-351 (Vyxeos^®) 0.6 mg/mL infusion solutions in prefilled 5% glucose infusion bags

Background and importance
CPX-351 (Vyxeos^®) is a fixed combination liposomal formulation of cytarabine (CYT) and daunorubicin (DNR) indicated for the treatment of acute myeloid leukaemia. It is marketed as a freeze-dried powder to be reconstituted and diluted prior to infusion. According to the SmPC, CPX-351 infusion solutions are physicochemically stable for only 4 hours at 2-8 °C. Prolonged stability data of ready-to-administer (RTA) infusion solutions are not yet published, but required in order to enable pharmacy-based preparation of CPX-351 infusion solutions in advance.

Aim and objectives
To investigate the physicochemical stability of 0.6 mg/mL CPX-351 RTA infusion solutions in 5% glucose (G5) bags, when stored firstly at 2-8°C for 14 days and subsequently at 25 °C for 7 days.

Materials and methods
0.6 mg/mL CPX-351 test solutions were prepared in triplicate by using Freeflex G5 infusion bags (final volume 50 mL). Test solutions were at first stored for 14 days at 2-8 °C, followed by 7 days at 25 °C. Directly after dilution, and after 4, 12, 24, 48, 72 hours, and 5, 7, 14, 15, 16, 21 days, samples were withdrawn and stability-indicating parameters analysed by complementary analytical methods: (i) total concentration of CYT/DNR (non-encapsulated + encapsulated) by HPLC-UV-Vis analysis after disruption of the liposomes with 80% MeOH + 20% acetic acid at 60 °C (specification: intact CYT/DNR ≥90% of the initial concentration); (ii) rate of non-encapsulated CYT/DNR by separating non-encapsulated CYT/DNR with ProbeQuant Sephadex G-50 centrifugation columns and subsequent quantitative analysis of the eluate after liposome disruption (specification: non-encapsulated CYT/DNR max.10% of the total concentration); (iii) integrity and absence of aggregation of liposomes by determination of hydrodynamic diameter, polydispersity index, and zeta potential via dynamic light scattering (DLS); (iv) absence of visible particles and colour changes by visual inspection.

Results
Total concentrations (non-encapsulated + encapsulated) of intact CYT/DNR remained at 100% CYT and 99% DNR of the initial concentrations after 14 days at 2-8 °C plus 7 days at 25 °C. Non-encapsulated CYT/DNR concentrations amounted to <10% after 14 days storage at 2-8 °C and 2 days at 25 °C. Based on the results of DLS measurements, no signs of liposome disintegration or aggregation were observed over the total period of 14 plus 7 days. Visual inspection revealed no particles or colour changes during the whole observation period.

Discussion and conclusion
Based on the results of the complementary analytical methods, 0.6 mg/ml CPX-351 solutions diluted with G5 revealed to be physicochemically stable for 14 days stored at 2-8 °C, followed by 2 days storage at 25 °C. This is enabling preparation in advance.