Development and validation of a non-linear IVIVC model for a diltiazem extended release formulation FDA-UMAB contract—223943401.

Abstract

To develop and validate internally an in vitro–in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg). Serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using ultraviolet detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Linear and non-linear (quadratic, cubic, and sigmoid functions) correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted diltiazem 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 II using purified water was found to be the most discriminating dissolution method. Significant intersubject (CV%>50) was observed for Cmax and AUC. The quadratic M/F IVIVC model provided a significant 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 was 12.4% and 9.2%, respectively. The prediction errors observed for Cmax and AUC suggest that the predictability of the quadratic IVIVC model is inconclusive, as such, external validation studies are required. Copyright © 2002 John Wiley & Sons, Ltd.