Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men

摘要

Objective: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since α1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. Materials and methods: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. Results: Mirabegron increased tamsulosin Cmax to 159% (90% confidence interval (CI) 143 - 177%), AUC∞ to 161% (90% CI 149 - 173%), and t1/2 to 116%. Tamsulosin reduced mirabegron Cmax to 85% (90% CI 71 - 103%) and AUC∞ to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. Conclusions: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.