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Pharmacokinetics of Inhaled Treprostinil Sodium in Healthy Volunteers

A. C. Nelsen

Kevin Laliberte

David Zaccardelli

S. K. Gotzkowsky

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Conference: 2011 PH Professional Network Symposium

Release Date: 09.22.2011

Presentation Type: Abstracts

A Nelsen, PharmD; K Laliberte, PharmD; D Zaccardelli, PharmD; SK Gotzkowsky, PharmD 
United Therapeutics Corp., Research Triangle Park, NC

RATIONALE: Inhaled Treprostinil (iTRE) is a prostacyclin analog recently approved for the treatment of Pulmonary Arterial Hypertension (PAH). Two studies characterized the pharmacokinetic (PK) profile of single doses of iTRE in volunteers.

METHODS: Eighteen subjects (7M, 11F) were enrolled in a three period cross over bioavailability (BA) study. The absolute BA of iTRE 18 and 36 mcg were compared to a 15 ng/kg/min (60 min) intravenous infusion of treprostinil.

Forty subjects (19M, 21F) were enrolled in a maximum tolerated dose (MTD) study of 54, 72, 78, 84, and 90 mcg of iTRE. PK sampling was collected for eight hours. Peak plasma concentration (Cmax), time to peak concentration (Tmax), and systemic exposure (AUCinf) were determined in both studies.

RESULTS: In the BA study, Cmax and AUCinf were dose proportional following a single administration of iTRE 18 or 36 mcg and resulted in 64% and 72% absolute systemic BA, respectively. The mean Tmax was 0.15 hr for both inhaled doses.

In the MTD study, iTRE was dose proportional for AUCinf (mean range: 0.661 to 1.579 ng*hr/mL) and Cmax (mean range: 790 to 1708 pg/mL). The mean Tmax was 0.20 hr across all doses. Adverse events of chest pain, chest discomfort, nausea, and vomiting in the 90 mcg cohort were determined to be intolerable, thus the MTD for a single dose of iTRE was 84 mcg.

ITRE remained detectable in the plasma approximately 4 hours after inhalation in both studies. Elimination half-life could not be calculated since a multi-compartment PK model could not be applied to the data. Using a non-compartment model, the apparent half-life ranged from 0.46 to 0.76 hr across both studies.

CONCLUSIONS: The plasma concentration profile of iTRE has been established in volunteers and shown to be proportional across the range of doses studied.

CLINICAL IMPLICATIONS: These data support a four times daily regimen used in PAH patients.

DISCLOSURES: All authors are employees of United Therapeutics Corp. This data was presented at ATS2010.