PURPOSE: Ambrisentan is an oral, once-daily, ETA-selective endothelin receptor antagonist that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms. Tadalafil is an oral, once-daily, phosphodiesterase type 5 (PDE-5) inhibitor currently under investigation for the treatment of PAH. Concomitant use of these two oral, once-daily therapies for PAH may be likely; therefore, this study was designed to assess the potential for pharmacokinetic (PK) interactions between ambrisentan and tadalafil.
METHODS: A 2-period crossover study was conducted in 26 healthy adults. Systemic exposure (AUC0-∞) and maximum plasma concentration (Cmax) were determined for both ambrisentan and its metabolite, 4-hydroxymethyl ambrisentan, following a single 10mg dose of ambrisentan and after 5 days of dosing with tadalafil (40mg qd). AUC0-∞ and Cmax were determined for tadalafil following a single 40mg dose of tadalafil and after 4 days of dosing with ambrisentan (10mg qd).
RESULTS: Ambrisentan Cmax was similar (+5.0%, 90% CI: -4.1% to +15.0%) and AUC0-∞ was slightly decreased (-12.5%; -16.0% to -8.8%) in the presence of tadalafil, compared to administration of ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan for both Cmax (+5.8%, -3.6% to +16.0%) and AUC0-∞ (-14.5%; -25.9% to -1.4%). Tadalafil Cmax (+0.6%: -5.6% to +7.1%) and AUC0-∞ (0.2%: -7.4% to +8.4%) were nearly identical in the absence and presence of ambrisentan. The overall safety profile was similar with concomitant administration of ambrisentan and tadalafil compared to either drug alone. Decreases in systemic blood pressure were observed for each drug, which did not appear to be additive or synergistic when coadministered.
CONCLUSION: Multiple doses of tadalafil had no clinically relevant effect on the pharmacokinetics of either ambrisentan or its metabolite, 4-hydroxymethyl ambrisentan. Similarly, multiple doses of ambrisentan had no clinically relevant effect on the pharmacokinetics of tadalafil.
CLINICAL IMPLICATIONS: Coadministration of ambrisentan and tadalafil should not require dose adjustments of either drug compared to administration alone.
DISCLOSURE: Rebecca Spence, Employee Authors are employed by Gilead Sciences, Inc.; No Product/Research Disclosure Information