Tosca Elena M, Rocchetti Maurizio, Pérez Elena, Nieto Conchi, Bettica Paolo, Moscoso Del Prado Jaime, Magni Paolo, De Nicolao Giuseppe
Department of Electrical, Computer and Biomedical Engineering, University of Pavia, via Ferrata 5, I-27100 Pavia, Italy.
Consultant, I-20100 Milano, Italy.
Pharmaceutics. 2021 Feb 12;13(2):255. doi: 10.3390/pharmaceutics13020255.
Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro-in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, Rvivo(t), was predicted from the in vitro profile through a nonlinear relationship. Rvivo(t) was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration-time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study.
卫生当局会在药品获得监管批准前后，仔细评估其批量生产过程中的任何变化。在缺乏充分的体外-体内相关性（A级IVIVC）的情况下，通常需要进行体内生物等效性（BE）研究，这会增加药物开发的成本和时间。本研究聚焦于为黄体酮阴道环（PVRs）建立A级IVIVC，这是一种设计用于体内持续给药的剂型。在两项临床研究中，评估了四批分别含有125、375、750和1500mg黄体酮且具有不同体外释放速率的阴道环的药代动力学（PK）。利用体内血清浓度和体外释放曲线，通过基于直接微分方程的方法和非线性混合效应方法，建立了群体IVIVC黄体酮环（P环）模型。通过非线性关系从体外曲线预测体内释放量Rvivo(t)。Rvivo(t)被用作描述黄体酮体内血清浓度动态的房室PK模型的输入。所提出的IVIVC P环模型能够从体外PVR释放曲线正确预测黄体酮的体内浓度-时间曲线。根据FDA对缓释口服药物IVIVC评估的接受标准，仔细评估了其内部和外部预测能力。所得结果证明，对于任何新的PVR批次的BE评估，可使用体外释放测试代替临床研究。最后，通过一个案例研究，探讨了所开发的群体IVIVC模型作为虚拟BE试验模拟器的可能用途。
