Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug‐Drug Interaction for Fesoterodine When Coadministered With Mirabegron

Abstract

5‐Hydroxymethyl tolterodine (5‐HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug‐drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies. Models predicted and verified mirabegron and desipramine (CYP2D6 substrate) and 5‐HMT and ketoconazole (strong CYP3A inhibitor) DDIs. Mirabegron model‐predicted mean steady‐state AUC and Cmax were within 11% of clinical observations. The predicted versus observed geometric mean ratio (GMR) of AUCinf for CYP2D6 substrates desipramine and metoprolol coadministered with mirabegron 100 or 160 mg once daily were 3.47 versus 3.41 and 2.97 versus 3.29, respectively, indicating that the mirabegron model can be used to predict clinical CYP2D6 inhibition. 5‐HMT fractional clearance by CYP3A and CYP2D6 was verified from clinical DDI studies with a potent CYP3A4 inhibitor (ketoconazole) and inducer (rifampicin) in CYP2D6 extensive and poor metabolizers and with a moderate CYP3A inhibitor (fluconazole) in healthy volunteers. 5‐HMT AUCinf and Cmax GMRs for fesoterodine DDIs were all predicted within 1.26‐fold of clinical observation, providing verification for the fesoterodine substrate model. The predicted changes in 5‐HMT AUCinf and Cmax ratios for 8 mg fesoterodine when coadministered with 50 mg mirabegron were 1.22‐fold and 1.17‐fold, respectively, relative to 8 mg fesoterodine given alone. This modest increase in 5‐HMT exposures by approximately 20% is considered clinically insignificant and would not require fesoterodine dose adjustment when coadministered with mirabegron within approved daily‐dose ranges.

Effects of combined treatment with fesoterodine and mirabegron in a pelvic congestion rat model: Results from in vitro and in vivo functional studies

“…For fesoterodine and mirabegron, this has been predicted based on well‐established physiologically based pharmacokinetic models (Simcyp). The increase in the peak plasma concentration and the area under the plasma concentration‐time curve of 5‐HMT following concomitant administration of mirabegron and fesoterodine was <25%, which was not considered to be a clinically relevant drug‐drug interaction for fesoterodine …”

“…Evidence supports that fesoterodine and 5‐HMT both bind bladder and detrusor tissue with higher affinity than the parotid gland competitively and reversibly, indicating their selectivity for the target tissues. Another modeling and simulation study showed that when fesoterodine and mirabegron were coadministered, predicted changes in 5‐HMT plasma concentrations were clinically insignificant, and did not warrant changes in the recommended daily dose of fesoterodine when given with mirabegron . Notably, no differences were observed in side effects reported in a clinical trial by treatment groups receiving nonselective or selective antimuscarinics alongside a β 3 agonist .…”

Fesoterodine for the treatment of overactive bladder: pharmacological bases and clinical results

“…Известно, что активация β-адренорецепторов нор адреналином, высвобождаемым из симпатических нервов, повышает уровень циклического аденозинмонофосфата в гладких мышцах, что является ключевым триггером для их расслабления [19]. В этой связи весьма перспективными представляются результаты первого исследования эффективности совместного применения при ГМП М 2 -, М 3 -холиноблокатора фезотеродина и β 3 -адреномиметика мирабегрона [20].…”