Predicting Pulmonary Pharmacokinetics of Inhaled Liposomal Treprostinil (L606) and Treprostinil Solution in Healthy Adult

Background: Liposome is known as a biocompatible and controlled-release formulation. Inhaled liposomal treprostinil (L606) resolves the issue of short-half life, and provides extended pharmacokinetic profile for 24-hr continuous treatment. Aim: A multi-compartment model was therefore established to predict the concentrations of L606 and treprostinil solution in pulmonary tissue compartment. Methods: A single-dose, crossover PK study was conducted in 12 healthy adult subjects. 51μg L606 and 54μg Tyvaso® were administered via oral inhalation. Blood samples were taken and analyzed by LC-MS-MS. With the previous PK data via iv infusion of treprostinil, the multi-compartment modeling was developed to predict the pulmonary pharmacokinetics of L606 and treprostinil solution. Results: L606 offers a sustained drug level in pulmonary tissue compartment and lasts for more than 10 hours along with plasma PK pattern. L606 at 51μg remained approx. 1.0 ng/mL in pulmonary tissue compartment. Pulmonary levels are higher than plasma. In contrast, treprostinil solution quickly reached a high concentration and declined in pulmonary tissue compartment, then remaining in equilibrium with plasma level. Conclusion: Simulation of L606 indicated a sustained pulmonary level as compared with the immediate-release formulation of treprostinil solution. The model shows the potential of predicting the pharmacological effects of inhaled L606 and Tyvaso®.