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

• Published in: Journal of clinical pharmacology 2019-11, Vol.59 (11), p.1505-1518
• Main Authors: Lin, Jian, Goosen, Theunis C., Tse, Susanna, Yamagami, Hidetomi, Malhotra, Bimal
• Format: Article
• Language: English
• Subjects: CYP2D6 protein; Cytochrome P450; Desipramine; Drug dosages; Drug interaction; Drug interactions; drug metabolism; drug‐drug interactions; Fluconazole; Ketoconazole; Metoprolol; modeling and simulation; overactive bladder; PBPK; Pharmacokinetics; pharmacokinetics and drug metabolism; Rifampin; Substrates
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.1438

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.