The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol

Krauwinkel, Walter; Dickinson, James; Schaddelee, Marloes; Meijer, John; Tretter, Reiner; Wetering, Jeroen van de; Strabach, Grégory; Gelderen, Marcel van

doi:10.1007/s13318-013-0133-1

Cited by 37 publications

(41 citation statements)

References 31 publications

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“…21 A study with metoprolol and mirabegron showed that the combination of multiple doses of mirabegron 160mg/day and a single dose of metoprolol 100mg/day showed an increase in the area under the curve (AUC) of metoprolol by 3.29 fold and mean increase in half-life from 2.96 hours to 4.11 hours. 29 Similar to metoprolol, there was a 3.41 fold increase in AUC of desipramine and mean increase in half-life from 19.5 hours to 35.8 hours after a 50mg single dose of desipramine was administered to patients having taken multiple doses of mirabegron 100mg/day. 29 Monitoring should also be employed with CYP2D6 substrates with narrow therapeutic indices such as thioridazine, flecainide, and propafenone.…”

Section: Drug Interactionsmentioning

confidence: 92%

“…29 Similar to metoprolol, there was a 3.41 fold increase in AUC of desipramine and mean increase in half-life from 19.5 hours to 35.8 hours after a 50mg single dose of desipramine was administered to patients having taken multiple doses of mirabegron 100mg/day. 29 Monitoring should also be employed with CYP2D6 substrates with narrow therapeutic indices such as thioridazine, flecainide, and propafenone. A dose adjustment is recommended when initiating digoxin with mirabegron.…”

Section: Drug Interactionsmentioning

confidence: 92%

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Mirabegron: A Beta-3 Agonist for Overactive Bladder

Bragg

Hebel²,

Vouri³

et al. 2014

Consult Pharm

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Objective To review the literature regarding the efficacy and safety of mirabegron for the treatment of overactive bladder (OAB). Data Sources A literature search was performed using MEDLINE (PubMed) prior to 12/31/2013 using the terms “mirabegron” and “randomized-controlled trial.” Study Selection/Data Extraction All published, double-blind, randomized controlled trials assessing mirabegron were included. Articles were reviewed and included if mirabegron was used as monotherapy and if the primary outcome analyzed drug efficacy. Data Synthesis The efficacy of mirabegron for the treatment of OAB has been demonstrated in the selected five randomized, placebo-controlled trials. The majority of these trials lasted 12 weeks in duration and compared various doses of mirabegron to placebo and/or tolterodine extended release (ER). Primary efficacy outcomes for the trials included mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Included trials showed statistically significant reductions in both efficacy outcomes for various doses of mirabegron when compared to placebo. Conclusion Based on the trials reviewed, mirabegron has been efficacious in reducing mean number of micturitions and incontinence episodes per 24 hours, as well as improved other secondary outcomes like OAB symptoms and quality of life measures. Common adverse drug events seen with mirabegron include: hypertension, nasopharyngitis, urinary tract infections, headache, constipation, upper respiratory tract infection, arthralgia, diarrhea, tachycardia, abdominal pain, and fatigue. Given the efficacy and safety data currently available, mirabegron represents a reasonable alternative to antimuscarinics for patients with OAB.Future studies are needed to determine the utility of mirabegron for OAB in a variety of demographics.

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Section: Drug Interactionsmentioning

confidence: 92%

Section: Drug Interactionsmentioning

confidence: 92%

Mirabegron: A Beta-3 Agonist for Overactive Bladder

Bragg

Hebel²,

Vouri³

et al. 2014

Consult Pharm

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“…The first was a phase 1 study assessing mirabegron pharmacokinetics after multiple doses (50 or 100 mg) over a period of 10 days in 12 healthy subjects (6 men and 6 women) . The second investigation included 2 studies . One was a DDI study using 2 CYP2D6 substrates (desipramine and metoprolol).…”

Section: Methodsmentioning

confidence: 99%

“…SIM‐desipramine and SV‐metoprolol compound models are available in Simcyp and were used without modification. The virtual population in Simcyp was designed to match the clinical study population as described previously . For the PBPK simulations in the CYP2D6 EM population in accordance with clinical design with CYP2D6 EM subjects, the Healthy Volunteer Population file was used by modifying the frequency of the CYP2D6 PM, intermediate‐metabolizer, and ultrarapid metabolizer phenotypes to 0.…”

Section: Methodsmentioning

confidence: 99%

“…In healthy individuals who are genotypically poor metabolizers (PMs) of CYP2D6, mean C max and AUC were approximately 16% and 17% higher, respectively, than in extensive metabolizers (EMs) of CYP2D6 . In vitro and clinical data have also characterized mirabegron as a moderate and time‐dependent inhibitor of CYP2D6 and a weak inhibitor of CYP3A . As a moderate CYP2D6 inhibitor, mirabegron increases the systemic exposure to metoprolol and desipramine after multiple and single dosing (C max increase of 79%–90% and AUC increase of 229%–241%) for both metoprolol and desipramine (Table ) .…”

Section: Mean Predicted Versus Observed Mirabegron Pharmacokinetic Pamentioning

confidence: 99%

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

Lin

Goosen

Tse

et al. 2019

The Journal of Clinical Pharma

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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.

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Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

Konishi

Minematsu

Nagasaka

et al. 2019

Biopharm & Drug Disp

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We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi‐elimination pathway mediated by CYP3A4, uridine 5′‐diphosphate‐glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug–drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta‐analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration–time profile for mirabegron in an sRI population (simulated area under the plasma concentration–time curve (AUC) was within 1.5‐times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12‐times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.

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The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol

Cited by 37 publications

References 31 publications

Mirabegron: A Beta-3 Agonist for Overactive Bladder

Mirabegron: A Beta-3 Agonist for Overactive Bladder

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

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

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