Development of a Population Pharmacokinetics-Based in vitro - in vivo Correlation Model for Drugs with Site-Dependent Absorption: the Acyclovir Case Study

Acyclovir is a Biopharmaceutics Classification System (BCS) class III antiviral agent which is only absorbed in the upper part of the gastrointestinal tract. This study aimed to establish a new in vitro - in vivo correlation (IVIVC) platform based on population pharmacokinetic modeling for drugs with site-dependent absorption using acyclovir as a model drug. Three types of sustained-release (SR; 500 mg) acyclovir tablets were prepared by the wet granulation method. The in vitro dissolution profiles of the acyclovir SR tablets and the immediate-release (IR; 200 mg) were determined by the paddle method and their in vivo pharmacokinetics were evaluated in Beagle dogs. A population pharmacokinetic model was developed using S-ADAPT. By separating the dissolution and absorption processes, the population pharmacokinetic model adequately described all the in vivo pharmacokinetic data and estimated the in vivo dissolution profiles. The changes of absorption rate over time after oral administration were also successfully estimated. The parameter estimates of the in vitro and in vivo drug releases were correlated by linear regression. Finally, the in vivo pharmacokinetic profiles were well predicted by the developed IVIVC model from the in vitro dissolution data with the prediction errors within 8.26% and 10.06% for the maximum plasma concentration ( C max ) and area under the plasma concentration-time curve (AUC), respectively. The present approach provides a better understanding of the in vivo absorption for drugs that have limited absorption window and may be useful for their new formulation design and development.