title: No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers.
abstract: Ambrisentan is a nonsulfonamide, ET(A)-selective endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), and tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor under investigation for treatment of PAH. Due to the potential combination use, the pharmacokinetic (PK) interactions between these two drugs were assessed in a crossover study in 26 healthy adults. Single-dose PK of ambrisentan (10 mg) and its metabolite, 4-hydroxymethyl ambrisentan, were determined in the absence and presence of multiple doses of tadalafil (40 mg QD). Similarly, single-dose PK of tadalafil (40 mg) were evaluated in the absence and presence of multiple doses of ambrisentan (10 mg QD). In the presence of tadalafil, ambrisentan maximum plasma concentration (C(max)) was similar (105.0% [90% CI: 95.9-115.0%]) and systemic exposure (AUC(0-infinity)) was slightly decreased (87.5% [84.0-91.2%]), compared with ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan. Tadalafil C(max) (100.6% [94.4-107.1%]) and AUC(0-infinity) (100.2% [92.6-108.4%]) showed no difference in the absence and presence of ambrisentan. The safety profile of the drugs combined was similar to that of either drug alone. No dose adjustments should be necessary when these drugs are coadministered. These results are in contrast to previous reports that the sulfonamide-based ERA bosentan can cause marked decreases in the exposure of tadalafil.
authors.affiliation: Gilead Sciences, Inc., Boulder, Colorado, USA. becky.spence@gilead.com
authors.forename: Rebecca
authors.initials: R
authors.lastname: Spence
authors.forename: Arun
authors.initials: A
authors.lastname: Mandagere
authors.forename: Brooke
authors.initials: B
authors.lastname: Harrison
authors.forename: Christopher
authors.initials: C
authors.lastname: Dufton
authors.forename: Ramesh
authors.initials: R
authors.lastname: Boinpally
mesh_terms: D000293:Adolescent; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002243:Carbolines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000009:adverse effects* / Q000493:pharmacokinetics*; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000068581:Tadalafil; D014665:Vasodilator Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D002243:Carbolines; D004338:Drug Combinations; D010666:Phenylpropionates; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D014665:Vasodilator Agents; D000068581:Tadalafil; C467894:ambrisentan; C542601:4-hydroxymethyl ambrisentan