Stamatopoulos Konstantinos, O'Farrell Connor, Simmons Mark J H, Batchelor Hannah K, Mistry Nena
Biopharmaceutics, DPD, MDS, GSK, David Jack Centre, Park Road, Ware SG12 0DP, UK.
School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Pharmaceutics. 2023 Mar 9;15(3):882. doi: 10.3390/pharmaceutics15030882.
A physiologically based biopharmaceutic model (PBBM) of a modified-release formulation of theophylline (Uniphyllin Continus 200 mg tablet) was developed and implemented to predict the pharmacokinetic (PK) data of healthy male volunteers by integrating dissolution profiles measured in a biorelevant in vitro model: the Dynamic Colon Model (DCM). The superiority of the DCM over the United States Pharmacopeia (USP) Apparatus II (USP II) was demonstrated by the superior predictions for the 200 mg tablet (average absolute fold error (AAFE): 1.1-1.3 (DCM) vs. 1.3-1.5 (USP II). The best predictions were obtained using the three motility patterns (antegrade and retrograde propagating waves, baseline) in the DCM, which produced similar PK profiles. However, extensive erosion of the tablet occurred at all agitation speeds used in USP II (25, 50 and 100 rpm), resulting in an increased drug release rate in vitro and overpredicted PK data. The PK data of the Uniphyllin Continus 400 mg tablet could not be predicted with the same accuracy using dissolution profiles from the DCM, which might be explained by differences in upper gastrointestinal (GI) tract residence times between the 200 and 400 mg tablets. Thus, it is recommended that the DCM be used for dosage forms in which the main release phenomena take place in the distal GI tract. However, the DCM again showed a better performance based on the overall AAFE compared to the USP II. Regional dissolution profiles within the DCM cannot currently be integrated into Simcyp, which might limit the predictivity of the DCM. Thus, further compartmentalization of the colon within PBBM platforms is required to account for observed intra-regional differences in drug distribution.
开发并实施了一种基于生理学的茶碱缓释制剂（优喘平持续释放片200毫克片剂）生物药剂学模型（PBBM），通过整合在生物相关体外模型——动态结肠模型（DCM）中测得的溶出曲线，来预测健康男性志愿者的药代动力学（PK）数据。通过对200毫克片剂的卓越预测，证明了DCM相较于美国药典（USP）装置II（USP II）的优越性（平均绝对误差倍数（AAFE）：1.1 - 1.3（DCM）对1.3 - 1.5（USP II））。使用DCM中的三种运动模式（顺行和逆行传播波、基线）可获得最佳预测结果，这些模式产生了相似的PK曲线。然而，在USP II使用的所有搅拌速度（25、50和100转/分钟）下，片剂均发生了广泛侵蚀，导致体外药物释放速率增加且PK数据预测过高。使用来自DCM的溶出曲线无法以相同的准确度预测优喘平持续释放片400毫克片剂的PK数据，这可能是由于200毫克和400毫克片剂在上胃肠道（GI）停留时间的差异所致。因此，建议将DCM用于主要释放现象发生在远端胃肠道的剂型。然而，基于总体AAFE，DCM再次显示出比USP II更好的性能。目前，DCM内的区域溶出曲线无法整合到Simcyp中，这可能会限制DCM的预测能力。因此，需要在PBBM平台内对结肠进行进一步分区，以考虑观察到的区域内药物分布差异。
