Mirabegron, a β₃-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder

Mirabegron (YM-178), currently in development by Astellas Pharma Inc, is an orally active β₃-adrenoceptor (AR) agonist for the potential symptomatic treatment of overactive bladder (OAB). Mirabegron demonstrates nanomolar EC50 values against the human β₃-AR in biochemical assays with potent selectivity over the β₁- and β₂-ARs. Originally developed as a treatment for diabetes, the development of mirabegron was later refocused to OAB. Cystometric experiments in rats reported a reduction in resting intravesical pressure and contraction frequency in anesthetized rats, without any effect on the amplitude of micturition contraction. Mirabegron also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction. Top-line results from clinical trials to date indicate that mirabegron has been well tolerated with significant efficacy in reducing the number of incontinence episodes and mean micturition frequency in patients. Evidence of cytochrome P450 (CYP)2D6 inhibition in clinical trials highlighted a concern for pharmacokinetic interaction with other drugs that are CYP2D6 substrates, as confirmed by a rise in the pharmacokinetic parameters of desipramine with concomitant administration of mirabegron. Mirabegron exhibits a novel mode of action in targeting the β₃-AR for bladder relaxation, and the studies and trials conducted to date suggest mirabegron as a promising new treatment in the management of OAB symptoms, such as increased urinary urgency and frequency, and urgency incontinence.