• ambrisentan;
  • tadalafil;
  • endothelin receptor antagonist (ERA);
  • phosphodiesterase type 5 (PDE-5) inhibitor;
  • pharmacokinetics;
  • pulmonary arterial hypertension (PAH)


Ambrisentan is a nonsulfonamide, ETA-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 (Cmax) was similar (105.0% [90% CI: 95.9–115.0%]) and systemic exposure (AUC0–∞) was slightly decreased (87.5% [84.0–91.2%]), compared with ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan. Tadalafil Cmax (100.6% [94.4–107.1%]) and AUC0–∞ (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. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4962–4974, 2009