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- Title
Potential for Pharmacokinetic Interactions Between Ambrisentan and Cyclosporine.
- Authors
Spence, R.; Mandagere, A.; Richards, D. B.; Magee, M. H.; Dufton, C.; Boinpally, R.
- Abstract
Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ETA-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 (Cmax) increased 1.5-fold, and area under the plasma concentration-time curve (AUC)0-τ increased twofold. Marginal increases were observed for CsA Cmax (906 vs. 1,014 ng/ml) and AUC0-τ (3.05 vs. 3.37 µg·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.
- Subjects
PHARMACOKINETICS; CYCLOSPORINE; P-glycoprotein; PULMONARY hypertension; POLYPEPTIDES
- Publication
Clinical Pharmacology & Therapeutics, 2010, Vol 88, Issue 4, p513
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1038/clpt.2010.120