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Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug‐Drug Interaction for Fesoterodine When Coadministered With Mirabegron
Author(s) -
Lin Jian,
Goosen Theunis C.,
Tse Susanna,
Yamagami Hidetomi,
Malhotra Bimal
Publication year - 2019
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1438
Subject(s) - pharmacology , cmax , pharmacokinetics , ketoconazole , drug interaction , cyp3a , chemistry , active metabolite , mirabegron , cyp3a4 , cyp2d6 , medicine , overactive bladder , cytochrome p450 , antifungal , alternative medicine , dermatology , metabolism , pathology
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 C max were within 11% of clinical observations. The predicted versus observed geometric mean ratio (GMR) of AUC inf 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 AUC inf and C max 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 AUC inf and C max 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.