Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers.
Treprostinil diethanolamine is an oral prostacyclin analog currently being evaluated for the treatment of pulmonary arterial hypertension (PAH). Treprostinil is metabolized primarily by cytochrome P450 (CYP) 2C8 with minor contribution from CYP2C9. It is expected that oral treprostinil will be administered with bosentan, approved for the treatment of PAH and known to induce CYP2C9 and 3A4. This study evaluated whether a drug interaction exists between oral treprostinil, bosentan, and its active metabolite Ro 48-5033 during co-administration. Twenty-four participants were randomized in a 3-way crossover study to oral treprostinil 1 mg twice daily, bosentan 125 mg twice daily, and oral treprostinil 1 mg twice daily and bosentan 125 mg twice daily. Treprostinil geometric mean ratios (GMRs) (90% confidence interval [CIs]) for steady-state AUC(0-12) and C(max) (combination/treprostinil) were 0.92 (0.83, 1.03) and 0.96 (0.83, 1.11), respectively, whereas bosentan GMRs (combination/bosentan) were 1.02 (0.95, 1.10) and 1.04 (0.94, 1.15), respectively, and Ro 48-5033 GMRs were 0.99 (0.93, 1.06) and 1.03 (0.94, 1.13). In conclusion, because the GMR and 90% CI are within the equivalence interval of 0.8 to 1.25, co-administration of oral treprostinil and bosentan did not result in a pharmacokinetic interaction for either agent.
Gotzkowsky
S Karl
SK
United Therapeutics Corporation, 55 T.W. Alexander Drive, PO Box 14186, Research Triangle Park, NC 27709, USA. kgotz@unither.com
Dingemanse
Jasper
J
Lai
Allen
A
Mottola
David
D
Laliberte
Kevin
K
D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D000077300:Bosentan; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D011464:Epoprostenol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000959:Antihypertensive Agents; D013449:Sulfonamides; D011464:Epoprostenol; D000077300:Bosentan; C427248:treprostinil