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

Ross L Walenga; Andrew H Babiskin; Heather J Boyce; Xin Feng; Ahmed Zidan; Nahid S Kamal; Xiaoming Xu; Myong-Jin Kim; Liang Zhao

doi:10.1016/j.jconrel.2024.12.049

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

J Control Release. 2024 Dec 23:S0168-3659(24)00904-0. doi: 10.1016/j.jconrel.2024.12.049. Online ahead of print.

Authors

Ross L Walenga¹, Andrew H Babiskin², Heather J Boyce³, Xin Feng⁴, Ahmed Zidan⁴, Nahid S Kamal⁴, Xiaoming Xu⁴, Myong-Jin Kim³, Liang Zhao²

Affiliations

¹ Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA. Electronic address: [email protected].
² Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
³ Division of Therapeutic Performance II, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
⁴ Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

PMID: 39722305
DOI: 10.1016/j.jconrel.2024.12.049

Abstract

Oxycodone hydrochloride (HCl) extended release (ER) tablet is an abuse-deterrent formulation that uses a physical barrier to make it more difficult to crush tablets prior to abuse via various routes. A previously conducted in vivo pharmacokinetics (PK) study showed that particle size exhibited significant effects on PK. Here, a computational modeling study using a novel combined computational fluid dynamics and physiologically based PK model was applied to better understand the mechanisms that produce differences in PK according to particle size and formulation type for nasally insufflated oxycodone HCl immediate release (IR) and ER _tablets. Dissolution data were collected using a United States Pharmacopeia (USP) Apparatus 4 to support model parameterization. The in vitro dissolution data showed that the number of powder layers in the bead-based system impacted the observed dissolution pattern for the finely milled (106-500 μm) ER formulations, but not the finely milled IR (106-500 μm) or coarsely milled ER (500-1000 μm) formulations. The model was validated via comparison of PK predictions with available in vivo PK data for finely milled (106-500 μm) IR and ER formulations in the 30 mg strength, a coarsely milled (500-1000 μm) ER formulation in the 30 mg strength, and a finely milled ER formulation in the 80 mg strength. Model predictions showed relative differences no greater than 3.3 % for maximum plasma concentration (C_max) and 14.9 % for area under the plasma concentration time curve from time zero to the last time point, as well as absolute differences no greater than 0.8 h for time to C_max. The residence time in the nasal cavity was predicted to be 1 h for finely milled ER formulations as compared with approximately 20 min for the finely milled IR and coarsely milled ER formulations. When differences in dissolution input data were considered, there were noticeable changes in PK predictions observed for the finely milled ER formulations, according to the different number of powder layers in the USP Apparatus 4. Overall, the results of this study suggest that biopredictive in vitro characterization of abuse deterrence via the nasal route for an oxycodone HCl ER tablet drug product may include methods to characterize dissolution and impacts of formulation on residence time in the nasal cavity.

Keywords: Abuse-deterrent formulation; Computational fluid dynamics; Dissolution; Nasal insufflation; Physiologically based pharmacokinetic; Residence time.