Treprostinil pharmacokinetics in rats are extended using inhaled prodrug formulations

Introduction : In a rat model of acute hypoxia-induced pulmonary arterial hypertension (PAH), inhaled lipid nanoparticle formulations of treprostinil prodrugs (TPD) were found to have a longer duration of activity (>>2h) compared to treprostinil (TRE). TPDs with alkyl chains of lengths C12, C14, and C16 yielded the longest extensions in activity. Here, we evaluated the plasma and lung PK in rats that received a single inhaled dose of these TPDs. Methods : Nebulized TRE solution and TPD formulations were administered (at 15 nmole/kg) to anesthetized-ventilated rats (6h studies) or to conscious rats by nose-only inhalation (24h studies). TRE and TPD concentrations in lung tissue and plasma were measured by HPLC/MS/MS. Results : Ventilated rats treated with nebulized TRE had the highest plasma C max (3.5 ng/ml) which occurred immediately after dosing and measurable levels of TRE were not seen beyond 4h in the plasma and by 6h in the lungs. Ventilated rats treated with nebulized TPDs had plasma TRE C max values ranging from 0.2 to 0.6 ng/mL. TPD lung levels at 6h ranged from 15 to 60 ng/mL. In the 24h studies, plasma concentrations of TRE when dosed with C14- and C16-TPDs were above 0.1 ng/mL for up to 24h, i.e., levels corresponding to activity in acute hypoxia studies. Conclusions : Inhaled TPDs are present in the lungs for an extended duration and are associated with the slow, sustained release of TRE into the blood. This PK profile is quite different than inhaled TRE and strongly suggests that long alkyl chain prodrug formulations of TRE will likely have prolonged pulmonary vasodilator activity in humans.