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Published on 23 March 2010

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Extended stability of bortezomib

teaser Reconstituted bortezomib vials are chemically and microbiologically stable for at least five days when prepared using a closed system transfer device

Sa¡nchez-Rubio Ferra¡ndez J
PhD
Pharmacy Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Fernandez

teaser Reconstituted bortezomib vials are chemically and microbiologically stable for at least five days when prepared using a closed system transfer device

Sa¡nchez-Rubio Ferra¡ndez J
PhD
Pharmacy Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Fernandez
Alonso JM
PhD
Laboratory Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Bautista Sanz
MP
PhD
Pharmacy Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Moreno Di­az R
PhD
Pharmacy Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Matilla Garci­a E
PhD
Pharmacy Department
Hospital Infanta Cristina
Parla (Madrid) Spain

Multiple myeloma (MM) is characterised by the neoplastic proliferation of a single clone of plasma cells engaged in the production of a monoclonal immunoglobulin. MM is the second most common haematological malignancy and is normally associated with bone pain, fractures, and other important features such as anaemia, hypercalcaemi and renal impairment.

Over the last few years, new drugs have emerged in the treatment of MM, such as thalidomide, lenalidomide and bortezomib. These novel drugs have been shown to be effective in relapsed and refractory patients, and are being used as first-line therapy in order to evaluate their ability to deliver enhanced quality of response, including higher complete remission rates, which may ultimately improve survival.[1]

Bortezomib (BTZ) is a first-in-class proteasome inhibitor approved in Europe for the treatment of refractory multiple myeloma and, as a result of the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma)[2] study, for previously untreated patients who are not candidates for high dose therapy plus stem cell transplantation.

BTZ 1.3mg/m2/day is administered for refractory patients 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. For treatment naive patients BTZ is administered combined with melphalan plus prednisone in six-week cycles with BTZ at days 1, 4, 8, 11, 22, 25, 29 and 32 for the first four cycles and at days 1, 8, 22, 29 for cycles 5-9.

BTZ is supplied as a sterile, lyophilised formulation in a glass vial containing 3.5mg of active product. This presentation does not fit the recommended dosage for the standard adult patient and therefore some wastage is inevitable. The product information states that the reconstituted vial is stable only for 8 hours when stored at <25°C and protected from light.

Bortezomib is a very expensive drug with a very high potential impact on healthcare budgets. A recent report from the National Institute for Health and Clinical Excellence (NICE) established a cost-effectiveness ratio up to £47,000 compared to high-dose dexamethasone for the treatment of MM.[3]

Avoidance of wastage of the residual amount in a vial could be an important strategy to save resources; the stability of bortezomib vials once reconstituted is a crucial issue in this context.

We undertook a study to evaluate the microbiological stability of reconstituted bortezomib injection to determine whether use of the residual amounts would be feasible in practice.

Chemical stability
BTZ is a boronic acid. Molecules of this type are relatively unstable and form tetrahedral boron adducts in the presence of nucleophilic agents such as water.

The pharmaceutical form of BTZ is a sterile, lyophilised formulation with mannitol as a bulking agent in a glass vial filled under nitrogen that limits oxidation of the drug prior to reconstitution. The product monograph suggests that chemical stability of the reconstituted vials is very limited. Nevertheless, there are literature reports of longer stability that suggest the
possibility of using the product beyond times established
by the manufacturer.

Andre et al[4] developed and validated an HPLC method for separating and quantifying BTZ and determined degradation of bortezomib under various conditions. This study concluded that BTZ stability is affected by temperature and light exposure. However, vials stored under refrigeration and protected from light suffered no colour change or precipitation and maintained
chemical stability for at least five days.

Walker et al[5] validated a reverse phase gradient stability-indicating liquid chromatographic method to quantify BTZ. After 42 days of storage vials remained colourless and clear and retained more than 95% of the initial BTZ concentration both refrigerated and at room temperature, although small amounts of product degradation occurred at room temperature.

Finally, Bolognese et al[6] performed a study on commercial BTZ samples by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon respectively. All the samples remained unchanged for a week. After this time commercial BTZ undergoes slow oxidative deboronation which partially inactivates the product. Low  temperature and limited contact with air slow the degradation process.

Microbiological stability
Another relevant issue for the reutilisation of residual amounts of the vials is that once reconstituted the vial could suffer microbiological contamination since BTZ vials do not contain any preservative agent. For this reason, the manufacturer recommends immediate use of the solution.

Further use of the vial contents is the responsibility of the pharmacist and therefore it is necessary to determine whether, after the reconstitution procedure, the vial contents remain sterile for the period of chemical stability.

We carried out a pilot study to determine microbiological stability for reconstituted BTZ injection under our normal working conditions. A BTZ (Velcade, Janssen- Cilag International) vial was reconstituted according to the manufacturer’s instructions in 3.5ml of NaCl 0.9% inside a laminar flow class IIB cabinet. We used a closed system transfer device (Phaseal, Carmel Pharma) for reconstitution and sampling. The application of this protective device for the reconstitution of cytotoxic agents combined with disinfection of the vial stopper can minimise bacterial inoculation compared with other devices.[7]

Samples were taken at days 0, 3, 7 and 10 (corresponding to days 1, 4, 8 and 11 of the treatment cycle). The residual amount of the drug solution was stored protected from light and under refrigeration (2-8ºC). We first made a microbiological culture by inoculating 0.5ml sample in THIO-T (thioglycollate broth medium, Bio Merieux) liquid medium and incubated it for 48 hours in a shaker incubator (37ºC). Aliquots of this culture were then grown in specific culture media using Petri dishes of COS-Columbia agar (Sheep blood agar, Bio Merieux) and PVX-Gelose (Chocolat Polyvitex, Bio Merieux) for up to 72 hours in the incubator. We evaluated the results by checking for the presence of bacterial colonies.

None of the cultures showed bacteriological growth during the study.

Conclusion and discussion
Our conclusion is that the BTZ reconstituted vial was microbiologically stable for at least eleven days under our working conditions. When taken together with the reported extended chemical stability this means that the same vial could be used for the first two doses of the cycle. This would represent a significant cost-saving and resource optimisation. However, it is important to emphasise that these results are not necessarily transferable to other centres because working protocols may differ. The results would need to be validated in each centre before extended use of reconstituted BTZ could be introduced.

References
1. Mateos MV. Expert Rev Hematol 2008;1(1):17–28.
2. San Miguel JF, Schlag R, et el. NEJM 2008;359:906–917.
3. Green C et al. Health Technol Assess 2009;13(Suppl.1):29–33.
4. André et al. Ann Pharmacother 2005;39(9):1462–6.
5. Walker et al. Can J Hosp Pharm 2006;59(suppl 1):62.
6. Bolognese et al. Adv Hematol 2009;2009:704928.
Epub 2009 Apr 14.
7. De Prijck et al. Letters in Applied Microbiology 2008;47:543–8.



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