Purpose: Acyclovir is a Biopharmaceutics Classification System (BCS) class III antiviral agent which is only absorbed in the upper part of the small intestine. The aim of this study was to develop a new in vitro in vivo correlation (IVIVC) platform for drugs with narrow absorption window using acyclovir as a model drug.
Methods: One immediate release (IR; 200 mg) and three sustained release (SR; 500 mg) with different composition of hydroxypropyl methylcellulose (HPMC) tablets were prepared by wet granulation method and utilized to establish the IVIVC. The in vitro dissolution profiles of the formulations were obtained by the paddle method at four-different dissolution media and their in vivo pharmacokinetics following oral administration were evaluated in Beagle dogs. Then, a population pharmacokinetic model incorporating in vivo dissolution was developed using S-ADAPT software. To describe the regional absorption, the absorption rate constant from the gut compartment to central compartment was allowed to change over time. To establish IVIVC, the parameter estimates of the in vitro and in vivo dissolution profiles were correlated by linear regression. The developed IVIVC model was internally validated using IR and three SR tablets.
Results: The in vitro dissolution and in vivo pharmacokinetic profiles were well fitted by dissolution model and population pharmacokinetic model, respectively. The in vitro and in vivo dissolution profiles were described by mixed-order kinetics. The parameter estimates for in vivo dissolution were well correlated by linear regression (r2>0.99) with those for in vitro dissolution profiles at water. Once IVIVC was established, the plasma concentration-time profiles of acyclovir were well predicted by the developed new IVIVC platform from in vitro dissolution profiles as input data. Monte-Carlo simulations were carried out for internal validation and prediction errors for Cmax and AUC of IR and three SR formulations were all within the acceptable range (90 to 110%) according to the FDA guidelines.
Conclusion: In the present study, a new IVIVC approach for drugs regionally absorbed in the gastrointestinal tract was developed and validated. This approach holds great promise for designing optimal release profiles for drugs which have narrow absorption window.
SEUNG EUN CHUNG– Master's Course, Sungkyunkwan university, Suwon-si
DAYOUNG LEE– Sungkyunkwan University
CHANG HO Song– Researcher, Sungkyunkwan University, Kyonggi-do
HYEONMYEONG JEONG– Graduate Student, Sungkyunkwan University, Suwon, Kyonggi-do
JONGKWON HAN– Sungkyunkwan university
BEOM SOO Shin– Sungkyunkwan University, Kyonggi-do