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, 17 (3), 631-42

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration With Zolpidem

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Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration With Zolpidem

Binfeng Xia et al. AAPS J.

Abstract

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max, T max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R (2) > 0.9). The predicted deviations (%) for C max, AUC0-inf, AUC0-20 min, and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

Figures

Fig. 1
Fig. 1
Schematic diagram of the a oral cavity PBPK model layout* and b the drug mass transfer processes included in oral cavity tissue compartments. *Boxes represent individual oral cavity compartments, the blue arrows symbolize the drug exchange between the perfused layers of individual compartments and systemic circulation, and the orange arrows mark the salivary flow in the oral cavity. Orange dashed arrows represent the transfer of API upon swallowing
Fig. 2
Fig. 2
Regression curves for a oral mucosa f ut and b diffusivity through mucosal tissue versus log10 of the octanol/water distribution coefficient at pH = 7.4 (logD pH = 7.4) based on the results obtained from in vitro mucosa permeability assays for nine compounds
Fig. 3
Fig. 3
Simulated surface response plot for the theoretical impact on the fraction absorbed via IO mucosa by the a oral cavity model parameters of tissue diffusivity and f ut after a single sublingual solution dose versus solubility and logD pH = 7.4 compared with an API particle radius of b 1 μm or c 10 μm after a single sublingual tablet dose (1 mg)
Fig. 4
Fig. 4
Simulated and observed mean Cp-time curves for zolpidem after a single 3.5-mg Intermezzo® sublingual tablet using a the new GastroPlus physiologically based IO absorption model, b a simple one-compartment oral cavity model, compared with simulated and observed PK profiles after c a single oral dose of a 3.5-mg zolpidem tablet. The comparison of simulated PK at the early absorption stage up to 1.5 h is shown in panel (d)
Fig. 5
Fig. 5
Simulated a total and regional fractions absorbed of zolpidem in Intermezzo® sublingual tablets; b time course (up to 1.5 h) of the cumulative amount of zolpidem dissolved, absorbed, entered portal vein, absorbed intraorally, and entered system circulation (SC); c amount of zolpidem dissolved in saliva, cumulative amount swallowed (in dissolved and undissolved forms), amount retained in the oral cavity, and the cumulative amount that entered systemic circulation up to 0.5 h after a single 3.5-mg Intermezzo sublingual tablet

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