Stabilität und Kompatibilität applikationsfertiger Zytostatikazubereitungen ausgewählter neuer Zytostatika
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Abstract
Ready-to-use parenteral preparations of anticancer medicinal products are typically pre-pared in pharmacy-based centralized aseptic preparation units. Microbiological stability of the preparations remains a primary issue and stability determining factor when assigning shelf lives to the preparations. For this reason, experimental studies were performed to evaluate the ability of four different pathogens (S. aureus, E. coli, P. aeruginosa, C. albicans) related to hospital infections to grow in ready-to-use, cytotoxic and non-cytotoxic parenteral products aseptically prepared in hospital pharmacies. Viability studies were performed under conditions that simulate optimal ones for the growth of micro-organisms (low drug concentrations, room temperature). In total 14 new anticancer small molecules and anti-cancer monoclonal antibodies were tested. Most of the drugs tested showed neither growth-retarding nor growth-supporting properties of the test organisms. An exception was trabectedin, which generated rapidly antibacterial activity.
Additional experiments with non-cytoxic drug preparations revealed that the selected strains lost viability in parenteral solutions containing vancomycin, phenylephrine or mid-azolam after a period of a few hours or days. Tranexamic acid solution and 50% w/v glucose solution generated species-specific antimicrobial activity. In the lipid containing emulsions, colony forming units increased rapidly. Low pH values and high osmolality are probably the reason for growth inhibition in midazolam and 50% glucose solutions, respectively. The an-timicrobial activity of phenylephrine solutions is caused by the excipient sodium metabisul-fite. According to the results, solutions for parenteral administration should be prepared under strict aseptic conditions and kept refrigerated whenever possible to inhibit the growth of any contaminating organism.
There are a number of originator publications and databases available dealing with the physicochemical stability of reconstituted and diluted cytotoxic preparations. A comprehen-sive information source in table format (STABIL-LISTE©) is compiled by the Pharmacy De-partment of University Medical Center in Mainz. In the updated version of STABIL- LISTE© 7th ed., 2015 information about the stability/compatibility of drug loaded beads as well as 13 recently approved anticancer drugs (alemtuzumab 10 mg/mL, amsacrine 1.5 mg/mL, belinostat, blinatumomab, cyclophosphamide Lyophilisat, nivolumab, obinutuzmab, pembrolizumab, plerixafor,ramucirumab, rituximab subcutaneous injection, trastuzumab subcutaneous injection trastuzmab emtansine) was added. Methods of data compilation are described, conflicting results and open questions were commented.
In order to reduce the adverse reactions of systemic chemotherapy, targeted transarterial administration (TACE) was introduced to treat patients suffering from HCC or liver metasta-ses of CRC. Simultaneous administration of the embolic and chemotherapeutic agents is achieved by drug eluting beads. DC Bead™ are marketed in different diameters ranging from 70-900 µm and can be loaded with cationic anticancer drugs. Prior to administration of the drug loaded beads, they are mixed with nonionic contrast medium to guide the embolic agent to the selected site of tumor. In order to guarantee the complete delivery of cytotoxic agents to the tumor site, compatibility and stability of the admixtures are prerogative. Therefore, the compatibility of epirubicin-loaded and irinotecan-loaded DC Beads™ (bead size 70-150 µm, 100-300 µm) with nonionic contrast media (Accupaque™ 300 (Iohexol), Imeron® 300 (Iomeprol), Ultravist® 300 (Iopromid), Visipaque™ 320 (Iodixanol)) commonly used by the interventional radiologists was experimentally tested. Results showed that it is feasible to prepare admixtures of epirubicin-loaded DC Bead (bead size 70-150 µm, 100-300 µm) with selected non-ionic contrast media in centralized cytotoxic preparation units in advance because of stability of admixtures over a period of 7 days. Admixtures of irinotecan-loaded DC Beads (bead size 70-150 µm) with different types and volumes of non-ionic contrast media are incompatible and should only be mixed immediately prior to delivery procedure by the radiologists.