In vitro-in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers.
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 modified-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 deconvolution-based 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.
Balan
G
G
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Route 206 & Provinceline Road, Princeton, NJ 08543, USA.
Timmins
P
P
Greene
D S
DS
Marathe
P H
PH
D000284:Administration, Oral; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D008687:Metformin