A phase 1, single-center, open-label, dose-rising clinical trial to evaluate the pharmacokinetics, safety and tolerability of treprostinil inhalation powder (TreT) in healthy normal volunteers

Abstract

Rationale: United Therapeutics is developing a new drug-device product comprising a dry powder formulation of treprostinil inhalation powder (TreT) and a small, portable, dry powder inhaler, to treat pulmonary arterial hypertension (PAH). Objectives: The primary objective was to evaluate the pharmacokinetics (PK), safety and tolerability of TreT in healthy normal volunteers (HNVs). Methods: This was an open-label, single ascending dose study in 36 HNVs, assigned to 6 single dose cohorts of TreT (30, 60, 90, 120, 150, and 180 µg). Safety and tolerability of TreT was evaluated in each cohort prior to escalating the dose for the next cohort. Blood samples were obtained before TreT administration and at selected times through 480 minutes post‑dose. Blood samples were analyzed for treprostinil using a validated analytical method and PK parameters were calculated using noncompartmental methods. Results: A total of 36 HNVs were randomized and dosed. There were no severe adverse events (AEs), serious AEs, or deaths during the study. No AEs led to a subject’s early termination. The most frequently reported AEs were cough (n=11, 30.6%) and headache (n=8, 22.2%). Bioanalysis confirmed that the treprostinil plasma concentrations and exposure for TreT, achieved clinically relevant concentrations comparable to those observed in historical Tyvaso single dose clinical studies. Cmax and AUC for treprostinil, increased in a linear manner with increasing dose. Conclusion: Overall, TreT was safe and well-tolerated and produced clinically relevant concentrations of treprostinil when inhaled as a dry powder.