Soyoung Shin(1), Tae Hwan Kim(2), and Beom Soo Shin(3)
(1) Wonkwang University, Korea, (2) Daegu Catholic University, Korea, (3) Sungkyunkwan University, Korea
Objectives: In vitro-in vivo correlation (IVIVC) is a predictive mathematical approach to establish a relationship between an in vitro dissolution and in vivo pharmacokinetics for a modified-release formulation [1, 2]. However, conventional IVIVC approaches are only applicable to highly permeable drugs that do not need to consider complex absorption processes [3]. Therefore, this study aimed at establishing a novel IVIVC approach for drugs with site-dependent absorption process based on population pharmacokinetic modeling by using acyclovir as a model drug.
Methods: Sustained-release (SR) tablets containing 500 mg of acyclovir designed to present fast, medium, and slow drug release were prepared via the wet granulation method. Hydroxypropyl methylcellulose was used as a drug release rate modifier. The in vitro dissolution properties of the three SR tablets and an immediate-release (IR; 200 mg) tablet were evaluated by the paddle method. The in vivo pharmacokinetics were assessed following oral administration in Beagle dogs. A population pharmacokinetic model was developed to characterize the dissolution, time-dependent absorption, and systemic disposition of acyclovir. The population pharmacokinetic parameters were estimated by simultaneously fitting all the obtained in vivo plasma concentration-time profiles to the population pharmacokinetic model using S-ADAPT.
Results: The in vitro drug release profiles were best described by Michaelis-Menten kinetics. The developed population pharmacokinetic model was able to describe all the in vivo plasma concentration-time profiles of acyclovir following oral administration of acyclovir formulations and allowed predicting in vivo dissolution profiles of acyclovir. The dissolution parameters representing the in vitro and in vivo drug releases were correlated by linear regression to establish IVIVC. Finally, the plasma concentration-time profiles of acyclovir were adequately predicted by the developed IVIVC model from the in vitro dissolution data. Prediction errors for the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) by comparing the population pharmacokinetic model predictions with the in vivo observations were all within 9.7% and 10.6%, respectively, satisfying the FDA criteria [1]. The final population pharmacokinetics-based IVIVC model also allowed to predict the in vivo absorption rates of acyclovir following oral administration. Acyclovir absorption was predicted to achieve its maximum absorption rate at 0.6 h, and then gradually decrease to zero after 1.8 h, indicating the presence of an absorption window.
Conclusions: A level A IVIVC has been successfully established for a drug that has a narrow absorption window. The superior flexibility of the population pharmacokinetic approach enabled separating the dissolution and absorption processes and including factors affecting each process. 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.
References:
[1] U.S. FDA, Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations, 1997.
[2] Kim TH et al. Journal of Pharmaceutical Investigation (2017) 48:431-441.
[3] Kim TH et al. Molecular Pharmacuetics (2017) 14:53-65.
Reference: PAGE 28 (2019) Abstr 8920 [www.page-meeting.org/?abstract=8920]
Poster: Drug/Disease Modelling - Absorption & PBPK