title: Potential for pharmacokinetic interactions between ambrisentan and cyclosporine.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc., Boulder, Colorado, USA.
authors.forename: R
authors.initials: R
authors.lastname: Spence
authors.forename: A
authors.initials: A
authors.lastname: Mandagere
authors.forename: D B
authors.initials: DB
authors.lastname: Richards
authors.forename: M H
authors.initials: MH
authors.lastname: Magee
authors.forename: C
authors.initials: C
authors.lastname: Dufton
authors.forename: R
authors.initials: R
authors.lastname: Boinpally
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D010666:Phenylpropionates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D065128:Endothelin Receptor Antagonists; D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D010666:Phenylpropionates; D011724:Pyridazines; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C467894:ambrisentan