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Potential for Pharmacokinetic Interactions Between Ambrisentan and Cyclosporine
Author(s) -
Spence R,
Mandagere A,
Richards D B,
Magee M H,
Dufton C,
Boinpally R
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2010.120
Subject(s) - ambrisentan , pharmacokinetics , pharmacology , cyp3a4 , endothelin receptor antagonist , steady state (chemistry) , chemistry , cmax , area under the curve , adverse effect , medicine , antagonist , bosentan , cytochrome p450 , endothelin receptor , receptor , metabolism
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–τ increased twofold. Marginal increases were observed for CsA C max (906 vs. 1,014 ng/ml) and AUC 0–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. Clinical Pharmacology & Therapeutics (2010) 88 4, 513–520. doi: 10.1038/clpt.2010.120