Quick and simple LC-MS/MS method for the determination of simvastatin in human plasma: application to pharmacokinetics and bioequivalence studies

Abstract

A simple, rapid, and sensitive method based on liquid chromatography-tandem mass spectrometry for the quantitative determination of simvastatin in human plasma was developed and validated. After a simple extraction with methyl tert-butyl ether, the analyte and internal standard (lovastatin) were analyzed using reverse-phase liquid chromatography, on a Kinetex C 18 column (100 × 4.6 mm, 2.6 μm) using acetonitrile: ammonium acetate (2 mM + 0.025 % formic acid) (70: 30, v/v) as a mobile phase in a run time of 3.5 min. Detection was carried out using electrospray positive ionization mass spectrometry in the multiple-reaction monitoring mode. The method was linear over 0.04-40.0 ng/mL concentration range. The mean extraction recovery of simvastatin was 82% (RSD within 15%). Intraday and interday precisions (as relative standard deviation) were all ≤8,7% with accuracy (as relative error) of ±8%. This rapid and reliable method was successfully applied for a bioequivalence study of 40 mg of simvastatin orally disintegrating tablets in 44 healthy volunteers, showing that this method is suitable for the quantification of simvastatin in human plasma samples for pharmacokinetics and bioequivalence studies.Uniterms: Simvastatin/determination. Liquid chromatography/quantitative analysis. Tandem mass spectrometry/quantitative analysis. Human plasma/determination of simvastatin. Simvastatin/ bioequivalence. Simvastatin/pharmacokinetics.Desenvolveu-e e validou-se um método simples, rápido e sensível baseado na cromatografia líquida acoplada à espectrometria de massas em tandem para a quantificação de sinvastatina em plasma humano. Após um simples preparo de amostras utilizando extração com éter metil-terc-butílico, o analito e seu padrão interno (lovastatina) foram analisados por cromatografia líquida de fase reversa, em uma coluna Kinetex C 18 (100 mm x 4,6 mm x 2,6 μm), utilizando uma fase móvel composta de acetonitrila:acetato de amônio (2 mM + 0,025% ácido fórmico) (70:30, v/v) em tempo total de corrida de 3,5 min. A detecção foi realizada por espectrometria de massas utilizando a ionização por electrospray no modo positivo e monitorando os íons pelo sistema de monitoramento de reação múltipla. O método apresentou linearidade na faixa de 0,4 -40,0 ng/mL. A recuperação média obtida para sinvastatina foi de 82% (DPR menor que 15%). A precisão intradia e interdias (como desvio padrão relativo) foi ≤8,7% com exatidão (como erro relativo) de ± 8%. Este método rápido e confiável foi aplicado com sucesso em um estudo de bioequivalência de comprimidos de desintegração oral de sinvastatina 40 mg em voluntários sadios, mostrando que este método é adequado para a quantificação de sinvastatina em plasma humano para estudos farmacocinéticos e bioequivalência.Unitermos: Sinvastatina/determinação. Cromatografia líquida/análise quantitativa. Espectrometria de massas em tandem/análise quantitativa. Plasma humano/determinação de sinvastatina. Sinvastatina/ bioequivalência. Sinvastatina/farmacocinética.

Pharmacokinetics and Bioequivalence of Fixed‐Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open‐Label Study in Healthy Volunteers

“…Furthermore, t 1/2 and t max were comparable in 20 Chinese healthy volunteers receiving 20 mg of simvastatin 44 . Similar simvastatin t max was also found in a study in Brazilian volunteers receiving 40 mg of simvastatin 45 …”

“…44 Similar simvastatin t max was also found in a study in Brazilian volunteers receiving 40 mg of simvastatin. 45 The mean plasma concentration of conjugated and total ezetimibe, as well as simvastatin and simvastatin β-hydroxy acid against the time profiles for the 3-period administrations of the reference and test formulations are represented in Figure 1. Simvastatin and its metabolite were eliminated abruptly during the first 48 hours, while ezetimibe with the longer t 1/2 was gradually eliminated throughout the 72 hours.…”