In vitro–in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers
✍ Scribed by Balan, Guhan (author);Timmins, Peter (author);Greene, Douglas S. (author);Marathe, Punit H. (author)
- Publisher
- John Wiley and Sons Inc
- Year
- 2001
- Tongue
- English
- Weight
- 177 KB
- Volume
- 90
- Category
- Article
- ISSN
- 0022-3549
- DOI
- 10.1002/jps.1071
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✦ Synopsis
The objective of the current study was to develop and evaluate the internal predictability for level C and A in vitro±in vivo correlation (IVIVC) models for prototype modi®ed-release (MR) dosage forms of metformin. In vitro dissolution data for metformin were collected for 22 h using a USP II (paddle) method. In vivo plasma concentration data were obtained from 8 healthy volunteers after administration of immediate-release (IR) and MR dosage forms of metformin. Linear level C IVIVC models were developed using dissolution data at 2.0 and 4.0 h and in vitro mean dissolution time (MDT). A deconvolution-based level A model was attempted through a correlation of percent in vivo input obtained through deconvolution and percent in vitro dissolution obtained experimentally. Further, basic and extended convolution level A IVIVC models were attempted for metformin. Internal predictability for the IVIVC models was assessed by comparing observed and predicted values for C max and AUC(INF). The results suggest that highly predictive level C models with prediction errors (%PE) of `5% could be developed. Mean percent in vivo input for metformin was incomplete from all formulations and did not exceed 35% of dose. The deconvolutionbased level A models for all MR formulations were curvilinear. However, a unique IVIVC model applicable to all MR formulations could not be developed using the deconvolution approach. The basic convolution level A model, which used in vitro dissolution as the in vivo input, had %PE values as high as 103%. Using an extended convolution approach, which modeled the absorption of metformin using a Hill function, a level A IVIVC model with %PE as low as 11% was developed. In conclusion, the current work indicates that level C and A IVIVC models with good internal predictability may be developed for a permeability-and absorption window-limited drug such as metformin.
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