PURPOSE: Tadalafil is an oral phosphodiesterase type 5 (PDE5) inhibitor approved for the treatment of erectile dysfunction and under investigation for the once-daily treatment of pulmonary arterial hypertension (PAH). Since bosentan is an oral, dual endothelin receptor antagonist indicated in the treatment of patients with PAH, this study determined whether pharmacokinetic interactions exist between tadalafil and bosentan.
METHODS: This was an open-label, randomized, three-period crossover pharmacokinetic drug interaction study. Healthy adult males (N=15; 19 to 52 years) received 10 consecutive days of either tadalafil 40 mg once-daily, bosentan 125 mg twice-daily, and the combination of tadalafil and bosentan. Each treatment period was separated by at least a 7-day washout. Serial blood samples were collected on Day 1 and Day 10 for measurement of tadalafil and bosentan plasma concentrations. Standard evaluation methods using point estimates and 90% confidence intervals (CI) determined the extent of any interaction between tadalafil and bosentan. Safety parameters were monitored.
RESULTS: Following 10 days of multiple-dose administration of bosentan and tadalafil, compared to tadalafil alone, the tadalafil equivalence ratio (90% CI) for AUCτ was 0.59 (0.55, 0.62) and for Cmax was 0.73 (0.68, 0.79), with no observed change in tmax. Following co-administration of bosentan with tadalafil, bosentan ratios for AUCτ and Cmax were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively, and fully contained within bioequivalence range for AUCτ (0.80-1.25) and Cmax (0.70-1.43). Once daily doses of 40 mg tadalafil alone and in combination with twice-daily doses of 125 mg bosentan for 10 days were generally well tolerated.
CONCLUSION: After 10 days of co-administration, bosentan decreased tadalafil exposure by 41.5% with no significant difference in bosentan exposure.
CLINICAL IMPLICATIONS: These pharmacokinetic differences are considerably less than those reported with another PDE5 inhibitor, sildenafil in combination with bosentan; whereby no dose adjustment is necessary (USPI, Tracleer®). Therefore, patients may receive concomitant tadalafil and bosentan therapy without dose adjustments.
DISCLOSURE: Rebecca Wrishko, Shareholder Eli Lilly and Company; Employee Eli Lilly and Company.