Physicochemical stability of lurbinectedin reconstituted at 500 μg/mL and diluted at 15, 30, and 70 μg/mL in 0.9% sodium chloride and 5% dextrose

Abstract

Background: Lurbinectedin (ZEPZELCA) is a cytotoxic, with alkylating properties. The commercially available pharmaceutical form is a glass vial containing 4 mg of lyophilized powder of lurbinectedin. The recommended dose of lurbinectedin is 3.2 mg/m2. For a 1.7-m2 body surface area, the average dosage is 5.44 mg. The manufacturer indicates a 30-hour stability for the reconstituted solution which cannot give the possibility to re-use the vial for the following days resulting in an average loss of 3600 € per preparation. Objectives: The first objective was to study the stability of 500 μg/mL reconstituted lurbinectedin in water for injection after storage at 2 to 8°C. The second objective was to study the stability of 15 to 70 μg/mL diluted lurbinectedin in 0.9% NaCl or dextrose 5% in water stored at 2 to 8°C. Methods: Three solutions in glass tubes for each condition (reconstituted 15 and 70 μg/mL solutions) were prepared. Due to the high cost, only 1 infusion bag at 30 μg/mL in polyolefin container was prepared. At each time of the analysis, 3 samples for each vial were analyzed by high-performance liquid chromatography coupled to a photodiode array detector. Physical stability was evaluated by visual and subvisual inspection (spectrophotometry). Results: The analytical method was validated according to International Conference on Harmonisation guidelines Q2 (R1). The 500 μg/mL lurbinectedin reconstituted solution retained more than 95% of the initial concentration after 14 days as the 15 to 70 μg/mL diluted solutions. No interaction between the polyolefin infusion bag and lurbinectedin was observed. No physical changes were observed both visually and subvisually. Conclusion: The reconstituted solution and the diluted lurbinectedin solutions were physically and chemically stable for 14 days when stored at 2 to 8°C protected from light. This new data makes it possible to re-use the reconstituted vial and to store a preparation in case of cancellation of an administration.

Physicochemical stability of pevonedistat at 50, 100 and 200 µg/mL diluted in 0.9% sodium chloride and at 10 mg/mL in partially used vials

“…Given that pevonedistat is still at an early access authorisation stage in France, we were not able to reserve vials exclusively for our study. To carry out this stability study we implemented a procedure similar to that used by Loeuille et al for the lurbinectedin study 4. Therefore, partially used vials concentrated at 10 mg/mL from the chemotherapy preparation unit were recovered to perform our stability study.…”

SFPO and ESOP recommendations for the practical stability of anticancer drugs: second update

“…These data allow production in advance, reuse of nonadministered preparations, and product savings. These stabilities concern the following products: 14 days for aflibercept, 3 90 days for atezolizumab, 4 28 days for cabazitaxel, 25,26 28 days for carfilzomib, 31 90 days for cetuximab, 35 28 days for daratumumab administered subcutaneously, 48 28 days for a durvalumab vial with a Spike device, 58 30 days for ipilimumab, 80,81 14 days for lurbinectedin, 84 10 days for a nivolumab vial with a Spike device, 96 14 days for omacetaxin, 97 7 days for paclitaxel albumin, 101 14 days for pembrolizumab, 102,103 28 days for pemetrexed diarginine, 105 14 days for pevonedistat, 107 and 21 days for trabectedin in a glass vial. 113…”

Stability

“…If the infusion is canceled, the financial loss is 11,250 €. A recent stability study demonstrated a 14-day stability for the reconstituted solution and the diluted solution for infusion allowing potential cost savings [123].…”