Novel Physiologically-Based Oral Cavity Model and Its Application for Projection of Clinical Pharmacokinetics of Intermezzo® Sublingual Tablets

Authors: Xia B, Yang Z, Zhou H, Lukacova V, Zhu W, Milewski M, Wu Y, Kesisoglou F
Conference: AAPS
Keywords: buccal, intraoral, intraoral absorption, PBPK, zolpidem
Software: GastroPlus®
Division: Simulations Plus

Introduction

Intraoral (IO) delivery refers to an alternative administration route that intends to deliver the drug substance through oral mucosa. The intraoral route provides several advantages over conventional oral dosage forms, such as prompt onset of action, avoiding extensive first-pass metabolism, and improved dosing convenience and patient adherence. There is an increasing interest to apply pharmacokinetic modeling and simulation to evaluate the bioperformance of IO dosage forms in clinics. Physiologically based pharmacokinetic modeling (PBPK) has been proven to provide valuable insights into oral formulation design and development. The purpose of this work was to develop and evaluate a novel physiologically based oral cavity model for projection and mechanistic analysis of clinical pharmacokinetics of intraoral formulations.

Methods: GastroPlus (version 8.0, Simulations Plus, Inc, CA, USA) with the Oral Cavity Compartment Absorption and Transit model (version beta 11) was used to simulate the plasma concentration vs time profiles and the fraction of intraoral drug absorption for a zolpidem tartrate sublingual tablet. Input for simulations included drug physicochemical properties (eg, solubility, permeability, LogP, pKa, API particle size) and systemic pharmacokinetic parameters (eg, clearance, volume of distribution, plasma and tissue binding), and intraoral absorption descriptors (eg, drug diffusivity, epithelium/saliva partition coefficient). The model performance was evaluated by comparing the simulated versus observed mean PK profile judged by visual inspection, correlation coefficient (R2) between predicted and observed profiles, and the deviation of the key PK parameters (Cmax, tmax, AUC; evaluated by prediction percent deviation). The structure of the physiologically based oral cavity model was described in Figure 1.

American Association of Pharmaceutical Scientists (AAPS), November 2-6, 2014, San Diego, CA

By Binfeng Xia, Zhen Yang, Haiying Zhou, Viera Lukacova, Wei Zhu, Mikolaj Milewski, Yunhui Wu, Filippos Kesisoglou