Stability of doripenem in vitro in representative infusion solutions and infusion bags

Abstract

Background: Doripenem, a new parenteral carbapenem with broad-spectrum antibacterial activity, is indicated for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. According to the US prescribing information, the carbapenems imipenem and meropenem are stable in sodium chloride for 4 hours.Objective: The aim of this study was to assess the stability of doripenem following constitution (50 mg/mL) and in injection solutions in vitro (0.9% sodium chloride and 5% dextrose) at a concentration of 5 mg/mL in room and refrigerated conditions.Methods: The stability of doripenem was assessed (1) under room-temperature conditions (25°C ± 2°C, 60% ± 5% relative humidity, under fluorescent light) immediately after constitution in vials with sterile water; (2) under room conditions and refrigerated conditions (5°C ± 3°C, 60% relative humidity, protected from light) immediately after constitution with sodium chloride or dextrose in 3 different infusion bags (polyvinyl chloride [PVC], PVC with vial adapter, and polyethylene); and (3) under room and refrigerated conditions using 500-mg doripenem vials that had been stored for 12 months in room temperature and protected from light before constitution with water and dilution in sodium chloride or dextrose injection. Doripenem 5 mg/mL and related substances (degradation products and impurities related to doripenem) were measured using a validated high-performance liquid chromatography method. Doripenem was considered stable if its concentration remained within 90% to 110% of the initial concentration and the total concentration of degradation products and impurities related to doripenem was ≤5%. Appearance of the solutions was assessed using clarity and comparison to color standards; pH, using standard methodologies; and particulate matter, using light-obscuration and microscopy.Results: Three lots of doripenem were assessed. Doripenem potency in constituted suspension (50 mg/mL) remained unchanged (means, 99.2% and 99.3%, respectively, of initial doripenem amount) for up to 60 minutes in room or refrigerated conditions prior to transfer to infusion bags. The doripenem 5-mg/mL infusion solution retained its potency for 12 and 72 hours under room and refrigerated conditions, respectively, in 0.9% sodium chloride injection, and for 4 and 48 hours under room and refrigerated conditions, respectively, in 5% dextrose injection (mean percentages of initial doripenem concentration, 95.5% and 96.6% under room and refrigerated conditions, respectively). Comparable results were obtained with vials of doripenem that had been stored for 12 months at room temperature and protected from light and then constituted (50 mg/mL). Doripenem 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection retained its potency in room conditions at the end of a 4-hour drip period when used with conventional infusion sets (mean, 96.6%) or Di(2-ethylhexyl)phthalate-free infusion sets (mean, 99.3%).Conclusions: Doripenem 5 mg/mL was stable for up to 12 hours in vitro in 0.9% sodium chloride at room temperature. Therefore, doripenem can be constituted, mixed with infusion fluids in the pharmacy, stored, delivered, and infused into a patient within a time frame suitable for 4-hour extended infusions.