Three-Period Bioequivalence Study of Sodium Levofolinate Injection With Calcium Levofolinate for Injection and Sodium Folinate for Injection in Healthy Chinese Subjects.

The aim of this study was to compare the bioequivalence and safety of test preparation sodium levofolinate injection with reference preparations of calcium levofolinate for injection and sodium folinate for injection in China. A single-center, randomized, open-label, 3-period, crossover test was conducted on 24 healthy subjects. Plasma concentration of levofolinate, dextrofolinate, and their metabolites l-5-methyltetrahydrofolate and d-5-methyltetrahydrofolate were quantified by a validated chiral-liquid chromatography-tandem mass spectrometry method. All adverse events (AEs) were documented to evaluate safety as they occurred and evaluated descriptively. Pharmacokinetic parameters (maximum plasma concentration, time to maximum concentration, area under the plasma concentration-time curve over the dosing interval, area under the plasma concentration-time curve from time 0 to infinity, terminal elimination half-life, and terminal rate constant) of 3 preparations were calculated. A total of 8 subjects (10 cases) of AEs occurred in this trial. No serious AEs or unexpected serious adverse reactions were observed. Sodium levofolinate was bioequivalent to calcium levofolinate and sodium folinate in Chinese subjects, and the 3 preparations were all well tolerated.

Stability of calcium levofolinate reconstituted in syringes and diluted in NaCl 0.9% and glucose 5% polyolefin/polyamide infusion bags.

PURPOSE: Calcium levofolinate (CaLev) for intravenous administration is commercially available as a powder that must be reconstituted for injection or reconstituted and then diluted before administration. The lack of stability data on CaLev solutions renders necessary extemporaneous manual preparation, preventing the use of automated/semi-automated systems, with a consequent loss in terms of quality and safety. METHODS: The present work assessed the chemical-physical and microbiological stability of CaLev prepared in sodium chloride 0.9%, glucose 5% and water for injections and stored in polyolefin/polyamide bags and polypropylene syringes at 2-8°C protected from light. For this purpose, we developed and validated a new rapid High Performance Liquid Chromatography with Ultra Violet Diode-Array Detection (HPLC-UV-DAD) method. RESULTS: The samples tested were stable for 14 days, retaining >95% of their initial concentration and showing no change in colour, turbidity or pH. Microbiological tests performed on the samples were negative. CONCLUSIONS: Our results confirmed the analytical stability of CaLev in NaCl 0.9%, glucose 5% and water for injection at concentrations used in clinical practice at our institute. This enables our centralized laboratory to organize the preparation of this drug in advance and the use of robots rather than manual preparation reduces the workload and the risk of preparation errors.

Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011.

OBJECTIVES: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. STUDY DESIGN: Retrospective analysis. METHODS: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. RESULTS: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. CONCLUSIONS: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.