# Mathematical Modeling of Local Drug Delivery in the Oral Cavity: From Release Kinetics to Mini-PBPK and Local PK/PD with Applications to Periodontal Therapies

## TL;DR

This paper introduces a mathematical model to understand how drugs behave in the mouth, linking drug release to their effects in periodontal treatments.

## Contribution

A novel mini-PBPK framework integrating drug release kinetics with local pharmacokinetics and pharmacodynamics in the oral cavity.

## Key findings

- The model captures drug adsorption to pellicle and diffusion within biofilm.
- It simulates clinical conditions like changes in gingival crevicular fluid flow due to inflammation.
- Case studies show the model explains drug retention and low systemic exposure in periodontal therapies.

## Abstract

Background/Objectives: Mathematical modelling provides a quantitative way to describe the fate and action of drugs in the oral cavity, where transport processes are shaped by salivary flow, pellicle formation, biofilm structure and the wash-out effect of gingival crevicular fluid (GCF). Local pharmacokinetics in the mouth differ substantially from systemic models, and therefore a dedicated framework is required. The aim of this work was to present a structured, physiologically based concept that links in vitro release testing with local pharmacokinetics and pharmacodynamics. Methods: A narrative review with elements of systematic search was conducted in PubMed, Scopus and Web of Science (1980–2025) for publications describing drug release, local PBPK, and PK/PD modelling in the oral cavity. Mathematical formulations were grouped into release kinetics, mini-PBPK transport and local PK/PD relations. Classical models (Higuchi, Korsmeyer–Peppas, Peppas–Sahlin) were integrated with a mini-PBPK structure describing saliva–mucosa–biofilm–pocket interactions. Results: The combined model captures adsorption to pellicle, diffusion within biofilm and wash-out by GCF. It allows simulation of variable clinical conditions, such as inflammation-related changes in QGCF, and links local exposure to pharmacodynamic outcomes. Case studies with PerioChip®, Arestin®, and Atridox® demonstrate how mechanistic models explain observed therapeutic duration and low-systemic exposure. Conclusions: The proposed mini-PBPK framework bridges empirical release data and physiological transport in the oral cavity. It supports rational formulation design, optimisation of local dosage, and personalised prediction of drug retention in gingival pockets. This modelling approach can become a practical tool for the development of dental biomaterials and subgingival therapies.