(M0930-10-56) Evaluating Food Effects in Oral Drug Delivery Using a Combination of PBPK Modeling and Molecular Dynamics Simulations

Purpose: The purpose of this study is to use predictive modeling techniques to understand the food effects encountered in oral drug delivery in regard to dissolution performance and bioavailability. This study combined physiologically-based pharmacokinetic (PBPK) modeling and molecular dynamics (MD) simulations to investigate the food effects for the poorly soluble drug fenofibrate in fasted and fed conditions. The overall objective is to develop an accurate and validated in-silico modeling approach to provide early insights into food effects and associated mechanisms in oral drug delivery.

Methods: Fenofibrate (FNF), a low solubility commercial drug compound, was selected for this study. FNF is a prodrug that gets rapidly metabolized to fenofibric acid (FNA) as the active metabolite [1]. In the study we used the amorphous solid dispersion (ASD) formulation of FNF with polyvinyl-pyrrolidone (PVP) [2,3].  Validated mechanistic physiologically-based pharmacokinetic (PBPK) models in fasted and fed male Sprague-Dawley rats were built to evaluate and compare the plasma concentrations of FNA. Furthermore, MD simulations of FNF-PVP ASD were modeled using the NAMD software package (v.3.0b3) with CHARMM36 and CGENFF all-atom force field parameters to investigate the drug dissolution in fasted-state simulated intestinal fluid (FaSSIF) and fed-state simulated intestinal fluid (FeSSIF).

Results: Fenofibrate is practically insoluble in water and is highly lipophilic. Several formulations have been developed to mitigate the food effects and enhance the bioavailability of this drug. Fig. 1 displays the mean plasma concentrations of FNA predicted by the PBPK model, following administration of 20 mg/kg dose of FNF in fasted rats. Fig. 2 compares the plasma concentration of FNA in fasted and fed conditions. The fed state predictions show an increase in the Cmax of FNA by 16% as compared to the fasted state.  This is corroborated by the MD simulation results shown in Fig. 3a, which reveal that FNF exhibits strong interactions with fed media, indicating higher miscibility in the fed state compared to fasted [4]. Additionally, the MD simulations show the formation of micellar-like aggregates, which affect the dissolution and dispersion of FNF in the fed state, aligning with the reported experimental observations (Fig. 3b)[4,5].

Conclusion: Our study demonstrates that predictive modeling can provide insights into examining drug dissolution behavior and the impact on bioavailability in the initial stages of drug development. Here we have combined two approaches, PBPK modeling and MD simulations to understand the food effect on the bioavailability of fenofibrate. The MD simulations shed light on the drug dissolution / release mechanism which can be coupled with pharmacokinetic modeling to predict drug exposure.

References: 1. Yun, H. Y., Joo Lee, E., Youn Chung, S., Choi, S. O., Kee Kim, H., Kwon, J. T., Kang, W., & Kwon, K. I. (2006). The effects of food on the bioavailability of fenofibrate administered orally in healthy volunteers via sustained-release capsule. Clinical pharmacokinetics, 45(4), 425–432.
2. Yousaf, A. M., Kim, D. W., Oh, Y. K., Yong, C. S., Kim, J. O., & Choi, H. G. (2015). Enhanced oral bioavailability of fenofibrate using polymeric nanoparticulated systems: physicochemical characterization and in vivo investigation. International journal of nanomedicine, 10, 1819–1830.
3. Hugo, M., Kunath, K., & Dressman, J. (2013). Selection of excipient, solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate. Drug development and industrial pharmacy, 39(2), 402–412.
4. Ranathunga D.T.S., Reynolds T., Konagurthu S. (2023), Predicting Drug Dissolution Performance Using Molecular Dynamics Simulations. AAPS PharmSci 360, Poster ID: W1030-03-20.
5. Jain, D., Thakur, P. S., Thakore, S. D., Samal, S. K., & Bansal, A. K. (2020). Impact of differential particle size of fenofibrate nanosuspensions on biopharmaceutical performance using physiologically based absorption modeling in rats. Journal of Drug Delivery Science and Technology, 60, 102040.

Acknowledgements: Equal contributions by Nairuti Milan Mehta (PBPK Modeling) and Dineli T.S. Ranathunga (MD Simulations).

Figure 1: Predicted vs observed mean plasma concentration – time profiles of fenofibric acid in fasted rats after oral administration of fenofibrate.

Figure 2: Plasma concentration – time profiles of fenofibric acid in fasted and fed state rats after oral administration of fenofibrate.

Figure 3: a) Drug-media interaction energy change with time in FNF-PVP ASD system. b) MD simulation snapshot demonstrating the formation of micellar-like aggregates in fed media as illustrated by the interaction energies.