Eddington N D, Marroum P, Uppoor R, Hussain A, Augsburger L
Pharmacokinetics Biopharmaceutics Laboratory, University of Maryland at Baltimore 21201-6808, USA.
Pharm Res. 1998 Mar;15(3):466-73. doi: 10.1023/a:1011988601696.
To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet.
In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation.
Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models.
The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.
在内部建立并验证一种亲水性基质缓释美托洛尔片的体外-体内相关性（IVIVC）。
采用以下方法检测美托洛尔片的体外溶出度：装置II，在pH 1.2和6.8条件下，转速50转/分钟；装置I，在pH 6.8条件下，转速100和150转/分钟。7名健康受试者服用三种美托洛尔制剂（100毫克）：缓释、中释、速释制剂以及一种口服溶液（50毫克）。在48小时内采集系列血样，并通过经过验证的采用荧光检测的高效液相色谱法进行分析。使用f2指标（相似性因子）分析溶出数据。利用来自不同制剂组合的累积溶出分数（FRD）和吸收分数（FRA）数据建立相关性模型。通过体内溶出速率的卷积获得预测的美托洛尔浓度。估计Cmax和AUC的预测误差以确定相关性的有效性。
发现装置I在150转/分钟转速和pH为6.8条件下是最具区分性的溶出方法。使用两种或三种制剂时，FRD和FRA之间存在显著的线性关系。所有IVIVC模型中，所有制剂的Cmax和AUC的平均预测误差百分比均小于10%。
观察到的Cmax和AUC相对较低的预测误差强烈表明美托洛尔IVIVC模型是有效的。平均预测误差百分比小于10%表明该相关性具有预测性，并允许将相关的溶出数据用作生物利用度研究的替代指标。
