Associate Computational Biologist United Therapeutics Corporation, United States
Disclosure(s):
Po-I Hsieh: No financial relationships to disclose
Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal, fibrotic lung disease characterized by the spatially heterogeneous stiffening of lung tissue. Treprostinil, a prostacyclin analog approved for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD), is under investigation for IPF when administered via inhalation (Nathan et al., 2022). Due to the spatially non-uniform progression of IPF, treprostinil distribution within lung tissue is a potentially important therapeutic factor that is difficult to measure clinically.
Modeling techniques such as multiple-path particle dosimetry (MPPD) and computational fluid dynamics (CFD) can simulate regional lung deposition of therapies but cannot be validated using plasma concentration data collected in clinical trials. To address this, we developed a hybrid model combining lung deposition with a published physiologically based pharmacokinetic (PBPK) model for oral and parenteral treprostinil (Wu et al., 2022), which had not previously included inhaled formulations. This framework enables prediction of lung deposition, regional respiratory tissue and systemic drug concentration profiles of inhaled treprostinil, supporting rational dose selection, delivery strategy, and translational modeling in trial planning.
Methods: We combined an MPPD model of inhaled treprostinil deposition in the lung with a PBPK model to describe systemic and regional pulmonary drug distribution. The MPPD model calculated deposition in the conducting airways, alveolar region, and gut, which were mapped to corresponding compartments in the PBPK model. The conducting airway and alveolar regions were each represented using four physiologically based subcompartments, enabling spatially and mechanistically informed absorption. Model parameters were estimated using clinical data across multiple treprostinil formulations and administration routes, including inhaled and parenteral.
Results: The model was validated using data from multiple treprostinil clinical trials, capturing pharmacokinetic (PK) profiles across inhaled and parenteral routes. By integrating a lung deposition model with a PBPK framework, we were able to simulate both pulmonary and systemic drug behavior following inhaled administration. The model also predicted how lung drug distribution, plasma concentrations, and acute hemodynamics are influenced by particle size and patient-specific PK characteristics. These simulations supported dose optimization and inhaler design across diverse patient populations.
Conclusion: We developed an integrated deposition-PBPK model for inhaled treprostinil that captures lung deposition and both regional tissue and systemic concentrations. The model demonstrated good agreement with observed clinical data.
Future work will expand this platform by integrating a spatial pharmacodynamic (PD) model to evaluate localized drug response within the lung. This will enhance our ability to link lung deposition with therapeutic outcomes for IPF.
Overall, this modeling approach offers a generalizable framework for simulating the behavior of inhaled therapies, supporting clinical development and inhaler design.
Citations: [1] Nathan, S. D., Behr, J., Cottin, V., Lancaster, L., Smith, P., Deng, C. Q., Pearce, N., Bell, H., Peterson, L., & Flaherty, K. R. (2022). Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis. BMJ Open Respiratory Research, 9(1), e001310. https://doi.org/10.1136/bmjresp-2022-001310
[2] Wu, X., Zhang, X., Xu, R., Shaik, I. H., & Venkataramanan, R. (2022). Physiologically based pharmacokinetic modelling of treprostinil after intravenous injection and extended-release oral tablet administration in healthy volunteers: An extrapolation to other patient populations including patients with hepatic impairment. British Journal of Clinical Pharmacology, 88(2), 587–599. https://doi.org/10.1111/bcp.14966
Keywords: Idiopathic pulmonary fibrosis, Physiologically based pharmacokinetics model, Deposition model
