The effect of different meal compositions on the oral bioavailability of treprostinil diolamine in healthy volunteers.
BACKGROUND
Treprostinil diolamine (oral treprostinil) is a prostacyclin analogue currently being evaluated for the treatment of pulmonary arterial hypertension as a sustained-release (SR) oral tablet. Previous data have demonstrated that the oral bioavailability of treprostinil was improved when taken with a meal containing at least 500 calories.


OBJECTIVE
As twice-daily intake of a high-fat, high-calorie meal may be undesirable or not feasible for some patients, this open-label, randomized, crossover study evaluated the effect of different meal compositions [a 500-calorie well-balanced meal (WB500), a 250-calorie well-balanced meal (WB250), a 250-calorie high-fat meal (HF250) and a 250-calorie well-balanced liquid meal (Ensure®)] on the relative bioavailability of oral treprostinil.


METHODS
Thirty-two healthy volunteers were administered a single 1-mg SR tablet of oral treprostinil immediately following each study meal. Each dose of oral treprostinil was separated by a 7-day washout period. Serial plasma samples were obtained over a 36-h postdose. Safety was assessed in all patients who received study drug.


CONCLUSIONS
Treprostinil plasma exposure (Cmax and AUC0-inf) decreased only slightly, 5-15% with decreasing caloric and increasing fat content. Headache was the most commonly reported prostacyclin-related adverse event (three reports).


CONCLUSIONS
Overall, there were no clinically significant differences in the relative bioavailability of oral treprostinil when administered immediately after meals containing 250-500 calories and 30-50% fat. These data support the administration of oral treprostinil with a meal containing as few as 250 calories and 30-50% fat, which is significant for ensuring patient convenience and compliance, particularly as consistency with regard to meals may impact oral treprostinil pharmacokinetics.
United Therapeutics, Research Triangle Park, NC.
A
A
Lim
L
L
Wang-Smith
J
J
Kates
A
A
Laurent
P
P
Kumar
K
K
Laliberte
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000494:pharmacology; D002149:Energy Intake; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005502:Food; D018565:Food-Drug Interactions; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009753:Nutritive Value; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000959:Antihypertensive Agents; D004041:Dietary Fats; D011464:Epoprostenol; C427248:treprostinil
UT-15C; food effect; oral treprostinil; treprostinil diolamine