PT-023 - DEVELOPMENT OF AN ADVANCED PBPK MODEL OF THE RESPIRATORY TRACT TO OPTIMIZE PULMONARY DELIVERY AND DOSING OF MO-OH-NAP TROPOLONE NANO-FORMULATION.

W. Aldhafiri¹, S. Singh², S. Haney¹, J. Ford³, S. Holstein², D. Murry⁴; ¹University of Nebraska Medical Center, University of Nebraska Medical Center, USA, ²University of Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, USA, ³the University of Utah School of Medicine in the division of Pediatric Hematology/Oncology, University of Utah School of Medicine in the division of Pediatric Hematology/Oncology, Salt Lake City, UT, USA, ⁴University of Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, USA.

Background: Pulmonary metastatic osteosarcoma (OS) is a significant therapeutic challenge due to complexity in targeting lung metastases. MO-OH-Nap tropolone (MO-OH-Nap) is a novel small molecule with potent cytotoxic activity across various OS cell lines. However, its poor solubility limits its clinical development. To overcome this, we developed a lipid-based nanoparticle (NP) formulation of MO-OH-Nap achieving substantial improvements in systemic exposure (AUC) and pulmonary delivery.
Our study aims to develop a precision dosing strategy for MO-OH-Nap by a permeability-limited pulmonary Physiological Based Pharmacokinetic (PBPK) model. The model details the respiratory tract, including the airways, alveolar spaces and the epithelial lining fluid (ELF). Drug transport between ELF, intracellular and interstitial space is modeled using surface area, membrane permeability, and first-order rate constants.

Methods: Pharmacokinetic and biodistribution data were obtained following single intraperitoneal (IP) or intravenous (IV) administration of MO-OH-Nap or its NP to CD-1 mice at doses of 5 mg/kg or 0.25 mg/kg, respectively. Plasma and lung tissue samples were collected over a 48 hr period. A validated LC-MS/MS method was used for quantitation of MO-OH-Nap concentrations. PK parameters were determined with PK-SIM® and Mobi software®. The PBPK model incorporates venous and arterial blood compartments along with 14 major tissues.

Results: MO-OH-Nap AUC for NP formulation was 28,229 and 991 hr*ng/mL, following IP and IV administration, respectively, which was significantly higher (~10 fold) compared to the MO-OH-Nap administration (2,748 and 180 hr*ng/mL). Following IP administration, systemic clearance of the NP formulation (184 mL/hr/kg), was reduced by ~10 fold compared to the unencapsulated drug (1791 mL/hr/kg). The simulated plasma and lung tissue AUCs were consistent with the observed AUCs (≤ 2 fold difference). Dosing simulations identified a NP dose of 7.5 mg/kg twice-weekly to achieve pulmonary AUC above the IC50 for 75% of the dosing interval.

Conclusion: The developed PBPK model accurately captured the distribution kinetics of MO-OH-Nap and its NP formulation to the lung compartments, optimizing lung-targeting dosing strategies. Further studies will evaluate NP formulation’s efficacy in treating metastatic pulmonary OS.