Stability of bortezomib reconstituted vials

Javier Sanchez-Rubio Ferrandez*1, Juan Manuel Fernandez Alonso2,
Marıa Dolores Martin3, Marıa Pilar Bautista Sanz1, Raquel Moreno Dıaz1, Elena Matilla Garcıa1

1Pharmacy; 2Clinical Laboratory; 3Microbiology Department,
Hospital Infanta Cristina, Parla, Spain

Background and objective: bortezomib (BTZ) is a peptidomimetic drug approved for the treatment of refractory multiple myeloma. BTZ 1.3 mg/m2/day is administered as an intravenous bolus in 21-day cycles, with twice-weekly administration for 2 weeks (days 1, 4, 8, 11), followed by a 10-day rest period. BTZ is supplied as a sterile, lyophilized formulation in a glass vial containing 3.5 mg. Therefore this presentation does not fit the recommended dosage. Product information states that reconstituted vial is stable for 8 h when stored at\25 C and protected from light. Due to its high cost, a study was conducted to determine if residual amounts of BTZ in vials can be stored and reutilized.

Design: to determine chemical stability a search in Medline was performed using Mesh terms ‘‘Drug Stability’’ and ‘‘Bortezomib’’. Manufacturer and abstracts of different congress were also consulted. To determine microbiological stability vial was reconstituted in 3.5 ml of NaCl 0.9% inside a class IIB cabinet. A closed system (Phaseal , Carmel Pharma) was used for reconstitution and sampling. Samples were taken at days 0, 3, 7 and 10 (days 1, 4, 8 and 11 of the cycle). Residual amount of the vial was stored protected from light and under refrigeration (2–8 C). 0.5 ml samples were first inoculated in THIO-T (tioglicolate broth medium, Bio Merieux) liquid medium and growed 48 h in a shaker incubator (37 C). Aliquots were growed in specific culture mediums using petri dishes [COS -Columbia agar  (Sheep blood agar, Bio Merieux) and PVX -Gelose Chocolat Polyvitex, Bio Merieux] up to 72 h in the incubator. Assay results were evaluated by checking the presence of any bacterial colonies

Results: three studies about chemical stability of BTZ were found. BTZ reconstituted vials proved to be chemically stable for 42 days in one of the studies and for at least 5 and 7 days in the other two studies. With regard to microbiological stability, none of the cultures showed bacteriological growth

Conclusions: BTZ reconstituted vials sustained chemical stability for at least 5 days and microbiological stability for at least 11 days under our working conditions. Same vial could be used for the first two doses representing significant cost-saving.

References
1. Bolognese, et al. An NMR study of the BTZ degradation under clinical use conditions. Adv Hematol. 2009.
2. Andre´, et al. Stability of BTZ 1-mg/ml solution in plastic syringe and glass vial. Ann Pharmacother. 2005.
3. Walker, et al. Stability of BTZ vials reconstituted with 0.9% sodium chloride at 4 C and room temperature. Can J Hosp Pharm. 2006.