Buchwald Peter
IVAX Research, Inc., 4400 Biscayne Blvd., Miami, Florida 33137, USA.
J Pharm Pharmacol. 2003 Apr;55(4):495-504. doi: 10.1211/002235702847.
A new, differential equation-based in-vitro-in-vivo correlation (IVIVC) method is proposed that directly relates the time-profiles of in-vitro dissolution rates and in-vivo plasma concentrations by using one- or multi-compartment pharmacokinetic models and a corresponding system of differential equations. The rate of in-vivo input is connected to the rate of in-vitro dissolution through a general functional dependency that allows for time scaling and time shifting. A multiplying factor that accounts for the variability of absorption conditions as the drug moves along is also incorporated. Two data sets incorporating slow-, medium-, and fast-release formulations were used to test the applicability of the method, and predictive powers were assessed with a leave-one-formulation-out approach. All fitted parameters had realistic values, and good or acceptable fits and predictions were obtained as measured by plasma concentration mean squared errors and percent AUC errors. Introduction of step-down functions that account for the transit of the dosage form past the intestinal sites of absorption proved useful. By avoiding the integral transforms used in the existing deconvolution- or convolution-based IVIVC models, the present method can provide increased transparency, improved performance, and greater modelling flexibility.
提出了一种基于微分方程的新型体外-体内相关性（IVIVC）方法，该方法通过使用单室或多室药代动力学模型以及相应的微分方程组，直接关联体外溶出速率和体内血浆浓度的时间曲线。体内输入速率通过允许时间缩放和时间偏移的一般函数依赖性与体外溶出速率相关联。还纳入了一个乘数因子，该因子考虑了药物移动过程中吸收条件的变异性。使用包含缓释、中释和速释制剂的两个数据集来测试该方法的适用性，并采用留一制剂法评估预测能力。所有拟合参数均具有实际值，通过血浆浓度均方误差和AUC误差百分比衡量，获得了良好或可接受的拟合和预测结果。引入考虑剂型通过肠道吸收部位转运的降阶函数被证明是有用的。通过避免现有基于反卷积或卷积的IVIVC模型中使用的积分变换，本方法可以提供更高的透明度、更好的性能和更大的建模灵活性。
