Nasal absorption of oxycodone predicted using a novel computational fluid dynamics-physiologically based...

Area of Science:

• Pharmacokinetics
• Computational Modeling
• Drug Delivery Systems

Background:

• Oxycodone hydrochloride (HCl) extended-release (ER) tablets are designed with abuse-deterrent features.
• Previous studies indicated particle size influences pharmacokinetic (PK) profiles.
• Understanding nasal route abuse deterrence mechanisms is crucial.

Purpose of the Study:

• To investigate the mechanisms behind particle size and formulation type effects on oxycodone HCl nasal PK using computational modeling.
• To compare immediate-release (IR) and ER formulations for nasally insufflated oxycodone HCl.
• To validate the computational model with in vivo PK data.

Main Methods:

• Utilized a combined computational fluid dynamics and physiologically based PK model.
• Incorporated in vitro dissolution data from United States Pharmacopeia (USP) Apparatus 4.
• Validated model predictions against existing in vivo PK data for various strengths and particle sizes.

Main Results:

• Model predictions for Cmax and AUC showed minimal relative differences (≤3.3% and ≤14.9%, respectively).
• Predicted nasal residence time was significantly longer for finely milled ER formulations (1 hour) compared to IR and coarsely milled ER (approx. 20 minutes).
• Dissolution patterns in USP Apparatus 4 varied with powder layers for finely milled ER formulations, impacting PK predictions.

Conclusions:

• Computational modeling effectively predicted PK differences based on particle size and formulation type for nasally administered oxycodone HCl.
• Nasal residence time is a critical parameter for abuse deterrence evaluation of ER formulations.
• Biopredictive in vitro methods should assess dissolution and formulation impacts on nasal residence time for abuse-deterrent drug products.