Kovacević Ivan, Parojcić Jelena, Homsek Irena, Tubić-Grozdanis Marija, Langguth Peter
Medicines and Medical Devices Agency of Serbia, Vojvode Stepe 458, Belgrade, Serbia.
Mol Pharm. 2009 Jan-Feb;6(1):40-7. doi: 10.1021/mp800128y.
The aim of the present study was to use gastrointestinal simulation technology and in vitro-in vivo correlation (IVIVC) as tools to investigate a possible extension of biowaiver criteria to BCS class II drugs using carbamazepine (CBZ) as a candidate compound. Gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus was used. Actual in vitro and in vivo data generated in CBZ bioequivalence studies were used for correlation purposes. The simulated plasma profile, based on the CBZ physicochemical and pharmacokinetic properties, was almost identical with that observed in vivo. Parameter sensitivity analysis (PSA) indicated that the percent of drug absorbed is relatively insensitive to the variation of the input parameters. Additionally, plasma concentration-time profiles were simulated based on dissolution profiles observed under the different experimental conditions. Regardless of the differences observed in vitro, the predicted pharmacokinetic profiles were similar in the extent of drug exposure (AUC) while there were certain differences in parameters defining the drug absorption rate (C(max)t(max)). High level A IVIVC was established for the pooled data set (r = 0.9624), indicating that 1% SLS may be considered as the universal biorelevant dissolution medium for both the IR and CR CBZ tablets. The proposed methodology involving gastrointestinal simulation technology and IVIVC suggests that there is a rationale for considering CBZ biowaiver extension and introduction of the wider dissolution specifications for CBZ immediate release tablets.
本研究的目的是使用胃肠道模拟技术和体外-体内相关性（IVIVC）作为工具，以卡马西平（CBZ）作为候选化合物，研究将生物豁免标准扩展至BCS II类药物的可能性。采用基于GastroPlus中实现的先进隔室吸收和转运模型的胃肠道模拟。将CBZ生物等效性研究中产生的实际体外和体内数据用于相关性分析。基于CBZ的理化性质和药代动力学性质模拟的血浆曲线与体内观察到的曲线几乎相同。参数敏感性分析（PSA）表明，药物吸收百分比对输入参数的变化相对不敏感。此外，根据在不同实验条件下观察到的溶出曲线模拟血浆浓度-时间曲线。尽管体外观察到差异，但预测的药代动力学曲线在药物暴露程度（AUC）方面相似，而在定义药物吸收速率的参数（C(max)、t(max)）方面存在一定差异。为合并数据集建立了高水平A的IVIVC（r = 0.9624），表明1%的十二烷基硫酸钠可被视为IR和CR CBZ片剂通用的生物相关溶出介质。所提出的涉及胃肠道模拟技术和IVIVC的方法表明，有理由考虑扩展CBZ的生物豁免并引入更宽泛的CBZ速释片溶出度规格。
