Cuesta-Gragera Ana, Navarro-Fontestad Carmen, Mangas-Sanjuan Victor, González-Álvarez Isabel, García-Arieta Alfredo, Trocóniz Iñaki F, Casabó Vicente G, Bermejo Marival
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
Department of Engineering, Pharmacy Section, Miguel Hernández University, Carretera Alicante Valencia km 87, 03550 San Juan de Alicante, Alicante, Spain.
Eur J Pharm Sci. 2015 Jul 10;74:86-94. doi: 10.1016/j.ejps.2015.04.002. Epub 2015 Apr 11.
The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations.
本文的目的是应用先前开发的、在NONMEM中实现的半生理药代动力学模型来模拟乙酰水杨酸（ASA）的生物等效性试验（BE），以便根据ASA人体实验数据验证模型性能。ASA是一种具有首过肝肠代谢的药物，遵循米氏动力学，会生成两代（第一代和第二代代谢物）两种主要代谢物。第一个目标是利用文献中的ASA药代动力学参数，在NOMMEN中对ASA的半生理模型进行调整，展示其顺序代谢过程。第二个目标是通过将NONMEM模拟得到的结果与已发表的1000 mg剂量实验数据进行比较，来验证该模型。经验证的模型用于模拟3种剂量方案（100、1000和3000 mg）以及6种与参比制剂相比体内溶出速率常数逐渐降低的受试制剂的生物等效性试验（kD 8 - 0.25 h(-1)）。最后，第三个目标是确定哪种分析物（母体药物、第一代或第二代代谢物）对制剂性能变化更敏感。验证结果表明，模拟得到的浓度-时间曲线与已发表的实验数据密切吻合，证实了模型性能。母体药物（ASA）是对药品质量下降最为敏感的分析物，受试制剂与参比制剂之间的Cmax和AUC比值下降幅度最大。
