(M1430-05-30) From In Vitro Dissolution Testing to In Vivo Clinical Pharmacokinetic Prediction Using PBPK Models for Oral Cavity Drug Products

Purpose: The oral cavity route of administration (ROA) enables drug absorption via the buccal, sublingual, and other oral mucosa, allowing for both local and systemic effects. This ROA is an attractive alternative to conventional oral (PO) administration, as it minimizes exposure of active pharmaceutical ingredients (APIs) to the acidic gastric environment, intestinal enzymes, and efflux transporters such as P-glycoprotein^{1. 2. 3. 4}. This project aims to develop a novel in vitro to in vivo extrapolation (IVIVE) method for oral cavity drug products (DP). This IVIVE is informed by data obtained within vitro dissolution measurements of oral cavity DP in artificial saliva.

Methods: Clinical pharmacokinetics (PK) in healthy subjects following intravenous (IV) and PO administration of sufentanil (SUF) and zolpidem (ZOL) were collected from the literature ^{5, 6, 7, 8}. The model parameters for systemic disposition of both compounds were sourced from published literature, built-in QSAR models in GastroPlus^® version 9.9 (Simulation Plus Inc., Research Triangle Park, North Carolina, USA), or fitted based on in vivo PK data. SUF and ZOL clearance and volume of distribution were validated using IV PK data, whereas their gastrointestinal absorption were validated using PO data. In both cases, the PBPK model captured the reported bioavailability (SUF~ 9% and ZOL~ 70%). These validated models were subsequently enhanced with Oral Cavity Compartmental Absorption and Transit (OCCAT™) models and were implemented to simulate sublingual (SL) administration of Dsuvia [Sufentanil sublingual tablet, Eq. 0.03 mg base] (SUF) and Edluar [Zolpidem sublingual tablet, Eq. 10 mg base] (ZOL). The enhancement for OCCAT incorporated diffusivity (Dm) and oral mucosal unbound fraction (fut) derived using IVIVE from EpiOral^TM tissue measurements ⁹. The parameters related to intraoral (IO) simulation settings (e.g., holding time, dosage forms) were derived from the clinical study designs reported in the literature. In vitro dissolution data were collected for both DPs in artificial saliva (pH 6.7; 60 ml) for 24 hours at 37^oC. The dissolution data was incorporated into the PBPK model using the Z-factor dissolution model. DP-specific Z-factor parameters were applied to simulate the clinical PK of SUF and ZOL following SL administration.

Results: Informing the baseline validated PBPK models with the in vitro dissolution measurements of Dsuvia and Edluar DP (Figure 1) helped to accurately predict the PK metrics (Cmax and AUCs) following their SL administration and to validate the IVIVE methodology (Figure 2 and Table 1. A parameter sensitivity analysis was conducted to explore potential causes of the slight underprediction of SUF Cmax. While oral cavity diffusivity had a minimal effect on systemic Cmax, physiological parameters such as oral mucosa thickness and study design factors (e.g., holding time) significantly influenced the systemic PK profile of SUF. Model-based analysis showed that SUF IO absorption(F_{a_IO}), accounted for approximately 30% of its total absorption following SL administration of Dsuvia (Figure 3), significantly enhancing its bioavailability compared to oral administration. In contrast, ZOL exhibited minor IO absorption (F_{a_IO}), under in vitro dissolution conditions due to slower disintegration and dissolution (Figure 1). Bioavailability remained unaffected, compared to oral administration, with the SL administration of Edluar (Figure 3). The in vivo results for ZOL in this work differ from those of Intermezzo SL tablet reported in previous research ¹⁰. These outcome variations are attributed to factors such as different DP formulations (Intermezzo vs Edluar), and IO conditions such as holding time. The PK profile of ZOL may be less sensitive to the amount absorbed from the oral cavity due to its high bioavailability (~70%) and moderate first-pass metabolism, compared to SUF which has a very low oral bioavailability (~9%) and high first-pass metabolism.

Conclusion: The integration of in vitro dissolution measurements for 2 specific oral cavity DPs, Dsuvia and Edluar, with PBPK models enabled accurate prediction of PK profiles after SL administration in healthy virtual subjects. This integration established a robust IVIVE for oral cavity DP. Future studies focusing on the translation of in vitro dissolution to the in vivo clinical outcomes with the utilization of PBPK modeling and in vitro dissolution measurements in artificial saliva, will help formulators to explore the impact of different excipients on product dissolution properties and critical biopharmaceutical properties that affect PK performance in vivo for oral cavity DP. This may impact the development of innovator and generic DP intended for oral cavity administration.

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2. Clinical Pharmacokinetics of Drugs Administered Buccally and Sublingually | Clinical Pharmacokinetics. Accessed April 2, 2025. https://link.springer.com/article/10.2165/00003088-199121020-00001
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Acknowledgements: The project was funded by a contract from the U.S. Food and Drug Administration (contract # 75F40120C00150).
Disclaimer: The views expressed here do not reflect official policies of the U.S. FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the U.S. Government.


Figure 1: In vitro dynamic dissolution measurements for Dsuvia (A) and Edluar (B) DPs over a course of 24 hours


Figure 2: Observed (Squares) and simulated (line) sufentanil (A) and zolpidem (B) plasma concentration-time courses in healthy subjects following a single sublingual administration of Dsuvia (A) and Edluar (B).


Figure 3: Compartmental absorption in the oral cavity and the different gastrointestinal segments following SL administration (30µg dose for sufentanil (A); 10 mg dose for zolpidem (B)) in healthy subjects.