OBJECTIVE:Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-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 C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) 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.
RCT Entities:
OBJECTIVE:Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-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 C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) 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.