Roudier B, Davit B M, Beyssac E, Cardot J-M
ESIEE Cités Descartes, BP 99, 93162, Noisy Le Grand Cedex, France,
Pharm Res. 2014 Sep;31(9):2529-38. doi: 10.1007/s11095-014-1349-8. Epub 2014 Mar 28.
In vitro in vivo correlation (IVIVC) is a biopharmaceutical tool recommended for use in formulation development. When validated, IVIVC can be used to set dissolution limits and, based on the dissolution limits, as a surrogate for an in vivo study. The purpose of this paper is to study the various methods used to fix dissolution limits.
Fixing dissolution limits is not a straightforward process; various approaches exist. The classical ±10% of dissolution limits was compared to the recommended ±10% of Cmax and AUC and to an innovative back calculation of the 90% CI. Based on simulated values the influence of the calculation method as well as of the variability of the results and pharmacokinetic processes was investigated.
Depending upon the method, the results are different and their comparison leads to possible rules. It appears that the usage of a back calculation of a 90% CI is an accurate and advantageous method when intra-individual variability associated with the drug is low. Those findings are in accordance with the current practice of IVIVC, which is not recommended for highly variable drugs.
The approach of using a 90% CI allows the intra-subject variability to be taken into account and fixes limits that ensure a greater chance to show acceptable BE, in case of reasonable intra-subject variability, leading to setting broader in vitro dissolution limits compared to classical solutions.
体外-体内相关性（IVIVC）是一种推荐用于制剂研发的生物制药工具。经过验证后，IVIVC可用于设定溶出限度，并基于这些溶出限度作为体内研究的替代方法。本文旨在研究用于确定溶出限度的各种方法。
确定溶出限度并非易事，存在多种方法。将经典的±10%溶出限度与推荐的±10%的Cmax和AUC以及一种创新的90%置信区间的反向计算方法进行比较。基于模拟值，研究了计算方法以及结果变异性和药代动力学过程的影响。
根据方法的不同，结果也不同，对其进行比较可得出可能的规则。当与药物相关的个体内变异性较低时，90%置信区间的反向计算方法似乎是一种准确且有利的方法。这些发现与IVIVC的当前实践一致，即不建议用于高变异药物。
使用90%置信区间的方法能够考虑个体内变异性，并确定限度，在个体内变异性合理的情况下，有更大机会显示可接受的生物等效性，与传统方法相比，会设定更宽的体外溶出限度。
