UCD School of Mathematical Sciences, University College Dublin, Dublin, Ireland.
J Pharmacokinet Pharmacodyn. 2011 Oct;38(5):519-39. doi: 10.1007/s10928-011-9206-4. Epub 2011 Jul 7.
In vitro-in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro and in vivo time scales.
在药物制剂开发、设定溶出度规范以及批准后变更的生物豁免申请过程中,体外-体内相关(IVIVC)模型被证明非常有用。最近提出了一种基于卷积的群体方法来开发 IVIVC,作为传统解卷积方法的替代方法,后者存在一些统计问题。本研究旨在使用基于卷积的时间缩放技术成功开发一种具有完全不同的体外和体内时间尺度的药物的 IVIVC 模型。体外和体内数据具有纵向性质,体内数据存在相当大的个体间变异性。该模型使用 NONMEM 软件包成功开发并拟合到数据中。通过将模型预测的血浆浓度-时间曲线与体内观察到的曲线进行比较来评估模型的实用性。该比较符合监管机构规定的内部和外部预测性的验证标准。本研究表明,当尝试为具有上述特性的数据开发 IVIVC 时,时间缩放方法可能是有用的。它还表明,基于卷积的群体方法非常灵活,并且能够生成具有体外和体内时间尺度差异很大的 IVIVC 模型。