Kádár Szabina, Kennedy Andrew, Lee Samuel, Ruiz Rebeca, Farkas Attila, Tőzsér Petra, Csicsák Dóra, Tóth Gergő, Sinkó Bálint, Borbás Enikő
Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 3 Műegyetem rkp, H-1111, Budapest, Hungary.
Pion Inc UK Ltd., Forest Row Business Park, Forest Row RH18 5DW, UK.
Eur J Pharm Sci. 2024 Jul 1;198:106782. doi: 10.1016/j.ejps.2024.106782. Epub 2024 May 1.
Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (C) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for C ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.
与简单溶出度测定相比，双相溶出和同步溶出-渗透（D-P）系统在改善体外-体内相关性方面都具有巨大潜力，但为了在药物研发中有效使用这些仪器，其测定条件和评估方法仍需完善。因此，本全面研究旨在比较小体积（16 - 20 mL）D-P系统和小体积（40 - 80 mL）双相溶出装置在五种含阿立哌唑（ARP）市售药品生物等效性预测中的预测准确性。研究了测定条件，特别是剂量依赖性，以克服这两种小规模系统的局限性。在双相溶出情况下，随着ARP剂量的降低，体内最大血浆浓度（C）预测有了很大改善，而在D-P装置中，使用整片药物与按比例缩小剂量的预测准确性相当。通过剂量降低策略，两种设备在C比值生物等效性预测中均能达到100%的准确性。在体内曲线下面积（AUC）预测方面，AUC比值的预测准确性不依赖于剂量，两种装置基于AUC结果预测生物等效性的准确性均为100%。本文首次提出，不仅通量测定的选定参数（如渗透率、初始通量、AUC值）被用作机理模型（胃肠道统一理论）的输入参数来预测吸收速率，而且整个体外通量曲线也被使用。在与体内数据比较期间，预测软件估计的所有吸收分数值均落在±15%的接受范围内。
