Zidan Ahmed, Siddique Abu Bakar, Shaklah Maha, Anand Om, O'Connor Thomas, Ashraf Muhammad
Office of Pharmaceutical Quality Research, OPQ, CDER, FDA, USA.
Office of Pharmaceutical Quality Research, OPQ, CDER, FDA, USA.
Eur J Pharm Biopharm. 2025 Nov;216:114874. doi: 10.1016/j.ejpb.2025.114874. Epub 2025 Sep 23.
In vitro-in vivo correlation (IVIVC) studies have been commonly used for assessing the impact of formulation and manufacturing changes on drug performance. The current study developed an IVIVC to establish patient-centric quality standards (PCQS) for dissolution using lamotrigine extended release (ER) 300 mg tablets as model formulation. Dissolution of Lamotrigine ER tablets was tested using various dissolution apparatus (USP II & III), dissolution media (biorelevant, non-bio relevant), media composition, pH, and hydrodynamics. The plasma lamotrigine concentration time profiles following oral administration were simulated using a physiologically based pharmacokinetic (PBPK) model. This PBPK model was developed and verified using plasma lamotrigine profiles following administration of lamotrigine intravenous (IV) solution and oral immediate-release (IR) tablets. Model verification results showed accurate prediction of Cmax and AUC following IV and IR lamotrigine administration with confidence level exceeding 95 %. Various IVIVC models were investigated using dissolution data of fast, medium, and slow ER lamotrigine 300 mg tablets manufactured in-house. Optimal IVIVC models were obtained using a second order polynomial and a two-compartment Loo-Riegelman deconvolution. The results of IVIVC goodness of fit showed that the dissolution condition in standard compendial media using USP apparatus II established a Level A IVIVC. This IVIVC model passed both internal and external validation criteria. Using these dissolution conditions, a PCQS of ≤10 % release at 2 h, ≤45 % at 6 h, and ≥80 % at 18 h was derived. In conclusion, this study demonstrates that a PCQS for lamotrigine ER tablets dissolution can be established using verified PBPK and validated IVIVC model and offers a reliable approach for assessment of product performance.
体外-体内相关性（IVIVC）研究通常用于评估制剂和生产变更对药物性能的影响。本研究开发了一种IVIVC，以拉莫三嗪缓释（ER）300毫克片剂作为模型制剂，建立以患者为中心的溶出度质量标准（PCQS）。使用各种溶出装置（美国药典II型和III型）、溶出介质（生物相关、非生物相关）、介质组成、pH值和流体动力学对拉莫三嗪ER片剂的溶出度进行了测试。口服给药后的血浆拉莫三嗪浓度-时间曲线使用基于生理的药代动力学（PBPK）模型进行模拟。该PBPK模型是使用拉莫三嗪静脉注射（IV）溶液和口服速释（IR）片剂给药后的血浆拉莫三嗪曲线开发和验证的。模型验证结果表明，静脉注射和口服拉莫三嗪后，Cmax和AUC的预测准确，置信水平超过95%。使用内部生产的快速、中速和慢速ER拉莫三嗪300毫克片剂的溶出数据研究了各种IVIVC模型。使用二阶多项式和两室Loo-Riegelman反卷积获得了最佳IVIVC模型。IVIVC拟合优度结果表明，使用美国药典II型装置在标准药典介质中的溶出条件建立了A级IVIVC。该IVIVC模型通过了内部和外部验证标准。使用这些溶出条件，得出了在2小时时释放≤10%、6小时时≤45%、18小时时≥80%的PCQS。总之，本研究表明，使用经过验证的PBPK和经过验证的IVIVC模型可以建立拉莫三嗪ER片剂溶出度的PCQS，并为评估产品性能提供了一种可靠的方法。
