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Potential for pharmacokinetic interactions between ambrisentan and cyclosporine.

Author(s): Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R

Affiliation(s): Gilead Sciences, Inc., Boulder, Colorado, USA.

Publication date & source: 2010-10, Clin Pharmacol Ther., 88(4):513-20. Epub 2010 Sep 1.

Publication type: Clinical Trial; Research Support, Non-U.S. Gov't

Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ET(A)-selective endothelin receptor antagonist (ERA) and a potential substrate for cytochrome P450 (CYP) 3A4, organic anion-transporting polypeptide (OATP), and P-glycoprotein (P-gp). Cyclosporin A (CsA), an inhibitor of CYP3A4, P-gp, and OATP, may be used concomitantly with ABS. In this open-label, parallel-treatment study, 28 healthy subjects received steady-state ABS (5 mg q.d.) either alone or with steady-state CsA (100-150 mg b.i.d.), and 24 other subjects received steady-state CsA either alone or with steady-state ABS. In the presence of CsA, ABS maximum plasma concentration (C(max)) increased 1.5-fold, and area under the plasma concentration-time curve (AUC)(0-tau) increased twofold. Marginal increases were observed for CsA C(max) (906 vs. 1,014 ng/ml) and AUC(0-tau) (3.05 vs. 3.37 microg.h/ml) in the presence of ABS. Frequent adverse events (AEs) were headache and gastrointestinal disorders. The addition of ABS to steady-state CsA appeared less tolerable as compared with the addition of CsA to steady-state ABS. A maximum ABS dose of 5 mg is recommended if it is coadministered with CsA. No change in CsA dose is recommended if it is coadministered with ABS.

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