Abstract: Poster Presentations |


Christopher Dufton, PhD*; Michael J. Gerber, MD; Ophelia Yin, PhD; Christine Brandquist, PharmD; Hossein A. Ghofrani, MD
Author and Funding Information

Myogen Inc., Westminster, CO

Chest. 2006;130(4_MeetingAbstracts):254S. doi:10.1378/chest.130.4_MeetingAbstracts.254S-c
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PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance and delay clinical worsening in a placebo-controlled study (ARIES-2) of patients with pulmonary arterial hypertension (PAH), with no incidence of serum aminotransferases >3xULN. Sildenafil is a phosphodiesterase type 5 inhibitor approved for PAH. Coadministration of sulfonamide-class ERAs have been shown to decrease (bosentan) or increase (sitaxsentan) the systemic exposure (AUC) of sildenafil, while sildenafil has been shown to increase the AUC of bosentan. Therefore, the potential for pharmacokinetic (PK) interactions between ambrisentan and sildenafil were examined.

METHODS: A 2-period crossover study was conducted in 19 healthy adults. Ambrisentan exposure (AUC0-last) and maximum plasma concentration (Cmax) were determined over a 24-hour period for a 10 mg dose of ambrisentan alone and after 7 days of dosing with sildenafil 20 mg tid. The AUC0-last and Cmax for sildenafil and n-desmethyl-sildenafil (active metabolite) were determined over a 24-hour period for a 20 mg dose of sildenafil alone and after 7 days of dosing with ambrisentan 10 mg qd.

RESULTS: Ambrisentan Cmax was unchanged (−3.7% [90% CI: −14.0% to +7.8%]) and a minor increase in AUC0-last (+6.0% [90% CI: +0.6% to +11.7%]) was observed after sildenafil administration. Sildenafil Cmax was increased slightly (+13.4% [90% CI: −0.4% to +29.1%]) and AUC0-last was unchanged (+0.4% [90% CI: −8.8% to +10.5%]) after ambrisentan administration; whereas, Cmax for n-desmethyl-sildenafil was unchanged (−0.4% [90% CI: −12.8% to +13.8%] and AUC0-last for n-desmethyl-sildenafil was slightly lower (−7.6% [90% CI: −14.9% to +0.4%]).

CONCLUSION: Multiple doses of ambrisentan had no clinically relevant effect on the pharmacokinetics of sildenafil or n-desmethly-sildenafil. Similarly, multiple doses of sildenafil had no clinically relevant effect on the pharmacokinetics of ambrisentan.

CLINICAL IMPLICATIONS: Coadministration of ambrisentan and sildenafil should not require dose adjustment of either drug compared to administration alone.

DISCLOSURE: Christopher Dufton, Employee Myogen, Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, ambrisentan.

Wednesday, October 25, 2006

12:30 PM - 2:00 PM




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