Ben Miles 1
1 Nanopharm (, United Kingdom)
Objectives
Intranasal delivery enables rapid systemic exposure, avoids hepatic first-pass metabolism, and can improve tolerability relative to oral and parenteral routes [1]. The Open Systems Pharmacology Suite (OSPSuite) is a widely adopted open-source modelling framework with extensive use [2]. Despite its extensive use for other dosage forms, a mechanistic, reusable physiologically-based pharmacokinetic modelling (PBPK) platform for intranasal dosing is not currently available within OSPSuite. This work aimed to develop a semi-mechanistic intranasal PBPK platform within MoBi that incorporates realistic nasal geometry. Intranasal sumatriptan powder was used as a proof of concept demonstration.
Methods
The nasal module represents four anatomical regions (vestibule, turbinates, olfactory region, and nasopharynx) derived from the Alberta Idealized Nasal Inlet (AINI) [3]. Each region includes nasal mucus, epithelial, and subepithelial compartments. Epithelial transport is permeability-limited whereas transfer from the subepithelium to systemic circulation is perfusion-limited. Tissue volumes are computed from AINI surface areas and literature tissue thicknesses [4]. Mucociliary clearance (MCC) was modelled as a first-order sink where region-specific clearance rates were derived from central cavity clearance and reported ciliary beat activity [1,5]. MCC transports undissolved solid drug to an oral absorption depot, capturing the swallowed fraction as a secondary systemic absorption pathway without explicit modelling of posterior mucosal transport. Dissolved drug remains available for epithelial uptake.
The effective epithelial permeability was calculated using the PK-Sim mechanistic permeability model and was not estimated during model development [6]. Systemic clearance and distribution parameters were estimated using intravenous clinical data [7] using the Levenberg-Marquardt algorithm [8], which were fixed for intranasal simulations. Oral pharmacokinetics (PK) of sumatriptan are known to exhibit complex absorption kinetics due to variable gastrointestinal transit and extensive first-pass metabolism, which are not adequately captured by a simple first-order depot model [9]. Therefore, oral parameters were adopted from published population pharmacokinetic analyses rather than re-estimated within the current framework [10], and solely used to represent the swallowed fraction arising from MCC. Regional deposition fractions were estimated from published scintigraphic data for the Breath Powered bidirectional device [11]. The particle dissolution rate was fitted to observed plasma profiles [12] from using the Levenberg-Marquardt algorithm [8].
Results
The two-compartment IV model predicted Cmax within 2.4% and AUC within 1.7% of observed PK data (15 min infusion of 3 mg). The predicted concentration-time profile was in good agreement with observed data across the full sampling period. For intranasal sumatriptan powder (delivered dose 16 mg [8]), AUC was predicted within 1.0% and Cmax within 22.9%. The model reproduced rapid early absorption associated with significant posterior deposition, but the biphasic absorption profile was incompletely captured. There was underprediction of the later phase, which was attributable to the limitations of the first-order oral depot for gastrointestinal absorption of the swallowed fraction. Local sensitivity analysis demonstrated that predicted Cmax and AUC varied approximately 89% and 88% respectively across ±50% variation in dissolution rate. In contrast, varying effective epithelial permeability produced only minor changes in PK outputs, indicating that formulation‑specific particle dissolution data are the dominant driver of predictive accuracy in this context.
Conclusion
An open-source semi-mechanistic intranasal PBPK platform was developed within MoBi and demonstrated for sumatriptan powder. To extend the capabilities of the platform, future updates will incorporate Noyes-Whitney particle-size-dependent dissolution and a more mechanistically advanced oral absorption model to more fully capture complex absorption kinetics. Following further verification across additional drug candidates and formulation types, the platform is intended as a contribution to the official OSP Suite GitHub repository.
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Reference: PAGE 34 (2026) Abstr 12075 [www.page-meeting.org/?abstract=12075]
Poster: Methodology - New Modelling Approaches