(374g) Integrated Digital Design of Efficacy and Optimal Treatment of Oral Drugs | AIChE

(374g) Integrated Digital Design of Efficacy and Optimal Treatment of Oral Drugs

Authors 

Rossi, F., Purdue University
Reklaitis, G. V., Purdue University
Nagy, Z., Purdue
The formulation of orally solid dosage forms is crucial for the pharmaceutical industry as it significantly impacts the performance of drugs. Formulation factors, including active pharmaceutical ingredients’ (API) particle size, excipient type, and crystallinity affect oral bioavailability [1,2]. Manufacturers develop various drug formulations to control release and enhance bioavailability (drug efficacy) during drug development. To develop drug formulations, scientists must bridge the in vitro formulation disintegration and dissolution and the in vivo absorption [3]. Several methods were proposed to achieve this [4-8], although in vitro-in vivo correlation (IVIVC) based approach are the most common applied [4,5]. However, a high number of dissolution tests and preclinical trials for animal and human studies are needed for this method. Recently, several studies have attempted to combine physiologically based pharmacodynamic-pharmacokinetic (PDPK) modeling with dissolution to guide formulation, although there are still some limitations due to the lack of a direct connection between the properties of formulation and absorption modeling [6,7,8]. In our work, we aim to combine the PDPK model for drug absorption, distribution, metabolism, and elimination (ADME) in vivo with the population balance model (PBM) for tablet disintegration and dissolution. This combined model allows us to predict the plasma concentration based on the formulation properties, which in turn helps us optimize the drug efficacy on the basis of product design and facilitate the formulation development process. As a result, a novel model for combining tablet-releasing and biological systems has been proposed. We demonstrate the impact of dissolution and disintegration effect on drug plasma concentration profile. The global sensitivity analysis indicates that the parameters of particle size distribution influence the drug plasma concentration. We further illustrate several scenarios to show how particle size distribution of crystals and granules impacts the drug concentration in different organs under different drug solubility, absorption mechanisms, and different amounts of initial liquid in the stomach. In conclusion, this model aids in uncovering the intricate interactions between formulation and biological systems, thereby holding promise for enhancing drug efficacy.

Acknowledgement: This work was supported by the National Science Foundation (NSF) under Grant No. 2132142

Reference

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