Single dose pharmacokinetics and absolute bioavailability of mirabegron, a ?3-adrenoceptor agonist for treatment of overactive bladder

Eltink, Charlotte; Lee, Jennifer; Schaddelee, Marloes; Zhang, Wenhui; Kerbusch, Virginie; Meijer, John; Marle, Sjoerd van; Grunenberg, Nicole; Kowalski, Donna; Drogendijk, T.; Moy, Selina; Iitsuka, Hiromi; Gelderen, Marcel van; Miyata, Hiroshi; Sawamoto, Taiji

doi:10.5414/cp201782

Cited by 47 publications

(48 citation statements)

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“…Sex differences in exposure could be explained by weight and absolute bioavailability. 4 The mean C max after a 50 mg dose of mirabegron under fasted conditions in male Japanese (study 2), Taiwanese (study 3), and Chinese (study 5) subjects was 35.37, 27.03, and 37.13 ng/mL, respectively. The mean AUC 0-1 was 387.13, 333.5, and 416.73 ng Á h/mL, respectively.…”

Section: Clinical Therapeutics 1040mentioning

confidence: 99%

“…7 Renal clearance accounts for approximately 25% of total clearance from plasma. 4 The rest of its elimination occurs through metabolism and excretion of unchanged drug in feces. Indeed, metabolism is one of the major elimination pathways of mirabegron.…”

Section: Clinical Therapeutics 1040mentioning

confidence: 99%

“…In addition, the pharmacokinetic parameters of mirabegron in healthy East Asian subjects in these studies were subsequently compared with those previously reported for Western healthy subjects. 4,5,8 …”

Section: Introductionmentioning

confidence: 98%

“…2 Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of β 3 -AR, which increases bladder capacity. 1,3 The pharmacokinetic profile of mirabegron after single and multiple oral doses has been reported in cohorts of Western, primarily white, 4,5 and Japanese 6 healthy adult subjects. Mirabegron had a greater than dose-proportional increase in mirabegron C max and AUC after single and multiple oral doses, which was due to an increase in absolute bioavailability with increasing dose.…”

Section: Introductionmentioning

confidence: 98%

“…Mirabegron had a greater than dose-proportional increase in mirabegron C max and AUC after single and multiple oral doses, which was due to an increase in absolute bioavailability with increasing dose. 4,5 Mirabegron was cleared by multiple mechanisms (renal and possibly biliary excretion of unchanged drug and metabolism by multiple enzymes), with no single predominating clearance pathway. 7 It has been reported that mirabegron oral controlled absorption system (OCAS) tablets exhibited a decrease in mirabegron plasma exposure with food in healthy Western subjects.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

Iitsuka

Gelderen

Katashima

et al. 2015

Clinical Therapeutics

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Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations.

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Section: Clinical Therapeutics 1040mentioning

confidence: 99%

Section: Clinical Therapeutics 1040mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

Iitsuka

Gelderen

Katashima

et al. 2015

Clinical Therapeutics

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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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The efficacy and safety of Vibegron in treating overactive bladder: A systematic review and pooled analysis of randomized controlled trials

Chen

Zhang

et al. 2020

Neurourology and Urodynamics

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Objective Vibegron is a new kind of β3‐adrenergic receptor agonist. We performed a systematic review and pooled analysis to assess the efficacy, safety, and tolerability of Vibegron for treating overactive bladder (OAB). Methods MEDLINE, the Cochrane Controlled Trial Register and EMBASE were used to pick out randomized controlled trials (RCTs) of Vibegron in treating OAB. The reference lists of the retrieved articles were also studied. We used RevMan version 5.3.0. to analyze the data. Results Three high‐quality RCTs involving a total of 2120 OAB patients were adopted in the systematic review and pooled analysis. The mean number of micturitions episodes/d (mean difference [MD] = −0.77; 95% confidence interval [CI] = −1.0 to −0.55; P < .00001); the mean number of urgency episodes/d (MD = −0.77; 95% CI = −1.03 to −0.52; P < .00001); mean number of urgency incontinence episodes/d (MD = −0.50; 95% CI = −0.64 to −0.35; P < .00001); mean number of incontinence episodes/d (MD = −0.45; 95% CI = −0.66 to −0.25; P < .0001); and mean volume voided/micturition (MD = 22.22; 95% CI = 17.36 to 27.07, P < .00001) showed that Vibegron was more efficacy in treating OAB than placebo. Dry mouth, drug‐related treatment‐emergent adverse event (TEAE), serious adverse event (SAE), and discontinuations due to adverse event (AE) suggested that Vibegron was well tolerated. Conclusions Our systematic review and pooled analysis demonstrate that Vibegron 75 mg or 100 mg/d statistically significant improved OAB symptoms. The treatment was well‐tolerated, with a favorable safety profile.

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Single dose pharmacokinetics and absolute bioavailability of mirabegron, a ?3-adrenoceptor agonist for treatment of overactive bladder

Cited by 47 publications

References 0 publications

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

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

The efficacy and safety of Vibegron in treating overactive bladder: A systematic review and pooled analysis of randomized controlled trials

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