Pharmacokinetics of 3 Times a Day Dosing of Oral Treprostinil in Healthy Volunteers

Abstract

Treprostinil diolamine (oral treprostinil) is an orally available prostacyclin analog that was developed for the treatment of pulmonary arterial hypertension. This study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of 3 times daily (TID) dosing of oral treprostinil. This was a 9-day, open-label, single-center study in which 19 healthy subjects received 0.5 mg oral treprostinil TID for 7 days. On the morning of day 1, subjects received a single 0.5 mg dose and on days 2-7, subjects received 3 doses of 0.5 mg oral treprostinil with a meal (at approximately 8 AM, 2 PM, and 8 PM). On the morning of day 8, subjects received a final 0.5 mg dose. Intensive 24-hour PK sampling occurred after the AM doses on days 1, 7, and 8. Additional trough plasma samples were collected before the morning and evening doses on days 4, 5, and 6. Nineteen subjects (9 men, 10 women) with a mean age of 35.2 years (range, 20-54 years) were enrolled. The majority of subjects were white (n = 17). The mean (% CVb) Cmax was 0.538 (37%), 0.714 (51%), and 0.559 (45%) ng/mL on days 1, 7, and 8, respectively. After a single dose on day 1 (first dose) and day 8 (last dose), mean (CVb%) AUC0-24 was 2.45 (26%) and 2.96 (28%) h·ng·mL, respectively. The mean (% CVb) steady-state AUC0-24 after TID regimen (on day 7) was 6.53 (34%) h·ng·mL, which was not significantly different from mean AUC0-∞ (7.39 h·ng·mL) on day 1 adjusted for 3 doses. Mean apparent t1/2 was similar on days 1, 7, and 8 (1.1-1.4 hours). Trough concentrations of treprostinil were comparable across study days ranging from 0.046 to 0.053 ng/mL before the AM dose and from 0.27 to 0.39 ng/mL before the evening dose. Steady state was achieved within 2 days of TID dosing. Treprostinil PK after TID dosing of oral treprostinil follows linear kinetics and can be predicted based on PK data after a single dose. Sixteen adverse events occurred in 7 subjects and included prostacyclin related adverse events such as headache, diarrhea, and jaw pain. Three times daily dosing of 0.5 mg oral treprostinil for 7 days was well tolerated in healthy subjects and provided sustained plasma exposure throughout the day at steady state without drug accumulation. This study provides data to support further evaluation of TID dosing regimen of oral treprostinil.