Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives

Mirabeg ron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC).

Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C _max) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed.

Mirabegron increased digoxin AUC and C_max by 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the C _max ratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and C _max by 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end.

No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.