A multicompartmemt lung model predicts pulmonary pharmacokinetics of inhaled liposomal treprostinil (L606) in healthy volunteer

Background: Current inhaled prostacyclins with short half-lives and immediate-release profile result in high peak-trough ratio and frequent dosing. Inhaled liposomal treprostinil suspension (L606) provides extended release and stable PK profile in healthy volunteer. In another PK-PD animal study, L606 indicated 12-hr extended reduction of PAP while the free drug solution at the same dose lasted for 4 hrs. Aim: A multicompartment physiologically based model was developed to predict the pulmonary pharmacokinetics of L606 and Tyvaso®. The simulation is attempted to quantitatively explain the extended effect of L606. Methods: A single-dose, open-label crossover PK study was conducted in 12 healthy adult subjects. 51 mcg L606 and 54 mcg Tyvaso® were administered via oral inhalation. Blood samples over 24 hrs post-dosing were taken and analyzed by LC-MS-MS. As combined with the previous human PK data via iv infusion, the multicompartment physiologically based model was developed to predict the pulmonary pharmacokinetics of L606 and Tyvaso®. Results: Simulation of 51 mcg L606 indicates a sustained drug level in pulmonary tissue which lasts for more than 10 hours. Treprostinil is estimated to be approx. 1.0 ng/mL and higher than the systemic plasma conc. and effective conc. (EC₅₀) of IP receptor (0.76 ng/mL). Tyvaso® reaches a high conc. in pulmonary tissue, then drops below 0.1 ng/mL quickly (in 2 hrs). Conclusion: The multicompartment physiologically based model provides a quantitative explanation for the 12-hr extemded effect. However, it needs to be confirmed on the patients with pulmonary arterial hypertension.