Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in
healthy adult volunteers.
Author(s): Gotzkowsky SK(1), Dingemanse J, Lai A, Mottola D, Laliberte K.
Affiliation(s): Author information:
(1)United Therapeutics Corporation, 55 T.W. Alexander Drive, PO Box 14186,
Research Triangle Park, NC 27709, USA. kgotz@unither.com
Publication date & source: 2010, J Clin Pharmacol. , 50(7):829-34
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.
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