RESUMEN
BACKGROUND: Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. The commonly used antimuscarinic drugs show poor patient compliance because of unsatisfactory potency, tolerability and high occurrence of adverse effects such as dry mouth, blurred vision, constipation, dizziness etc. Mirabegron is the first approved ß3-adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. OBJECTIVE: The present review provides an insight into the mechanism, pharmacokinetics, toxicokinetics, clinical trials and the development of various conventional and modified-release dosage forms of mirabegron for the treatment of overactive bladder syndrome. RESULTS: The clinical trials of phase II and phase III of mirabegron demonstrated symptomatic relief from the overactive bladder without disturbing the micturition cycle. To date, mirabegron showed promising results for safety, tolerability and efficacy in patients with overactive bladder syndrome. The modified-release tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs like Oxybutyline chloride ER, Detrol LA, VESIcare, etc. Conclusion: Mirabegron shows a distinct mode of action, i.e., targeting ß3-adrenoreceptors and improving bladder storage without altering void contractions. The limited side effects, high safety, efficacy and tolerability of mirabegron present an adequate substitute to antimuscarinics. However, long-term analysis and clinical studies are prerequisites for assessing the safety, tolerability and efficacy profile of mirabegron.
Asunto(s)
Acetanilidas/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Tiazoles/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/administración & dosificación , Acetanilidas/efectos adversos , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Animales , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/farmacocinética , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Agentes Urológicos/efectos adversos , Agentes Urológicos/farmacocinéticaRESUMEN
INTRODUCTION: Mirabegron, a selective ß3-adrenoreceptor agonist, is a well-established alternative to antimuscarinics in adults with overactive bladder (OAB) symptoms and is under development for use in pediatric patients. Understanding drug pharmacokinetics (PK) in pediatric patients is needed to determine appropriate dosing. Conducting these studies is ethically complex, particularly as regulatory guidance requires that PK is assessed in pediatric patients with a therapeutic need for the drug. It is also vital to evaluate the safety/tolerability and palatability/acceptability of pediatric formulations. PURPOSE: The purpose of the study was to characterize the PK of mirabegron in pediatric patients with neurogenic detrusor overactivity or idiopathic OAB, to provide a basis for a weight-based dosing algorithm, and to evaluate the safety, tolerability, and palatability/acceptability of the formulations. MATERIALS AND METHODS: A preliminary population PK model constructed from adult data with allometric scaling was used to predict single weight-adjusted mirabegron doses. This was developed to achieve exposures in pediatric patients in two phase 1 studies that were consistent with steady state in adults following once-daily 25 mg ('low dose') and 50 mg ('high dose') dosing. In study 1, adolescents (12-<18 years) and children (5-<12 years) received a single tablet under fed or fasted conditions. In study 2, children (3-<12 years) received a single oral suspension dose under fed conditions. The PK data were used to assess the predictive value of the preliminary PK model and to update it to analyze mirabegron PK in pediatric patients. The safety/tolerability and palatability/acceptability of the formulations were evaluated. RESULTS: Forty-three patients comprised six study cohorts: adolescents, low-dose tablets, fed (n = 7); children, low-dose tablets, fed (n = 7); adolescents, high-dose tablets, fed (n = 8); children, high-dose tablets, fed (n = 6); children, high-dose tablets, fasted (n = 6); and children, high-dose oral suspension, fed (n = 9). The population PK model-based doses for tablets and oral suspension achieved exposures that were typically consistent with steady state in adults. The final population PK model was used to describe the PK for mirabegron in pediatric patients (Table). Both formulations were well tolerated, and there were no reports of bad taste or swallowing difficulties for the tablets, although some found the oral suspension unpleasant. CONCLUSIONS: The single, weight-adjusted pediatric mirabegron doses were successfully predicted by population PK modeling to achieve drug exposures comparable with steady state in adults. The finalized PK model used to characterize the pediatric PK of mirabegron will be utilized to develop a weight-based dosing algorithm. The single mirabegron doses were well tolerated.
Asunto(s)
Acetanilidas/farmacocinética , Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Tiazoles/farmacocinética , Tiazoles/uso terapéutico , Vejiga Urinaria Neurogénica/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/efectos adversos , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Tiazoles/efectos adversos , Vejiga Urinaria Neurogénica/complicaciones , Vejiga Urinaria Hiperactiva/complicacionesRESUMEN
BACKGROUND: White adipose tissue (WAT) browning confers beneficial effects on metabolic diseases. However, visceral adipose tissue (VAT) is not as susceptible to browning as subcutaneous adipose tissue (SAT). AIM: Interpreting the heterogeneity of VAT and SAT in brown remodeling and provide promising lipid targets to promote WAT browning. METHODS: We first investigated the effects of ß3-adrenergic stimulation by CL316,243 on systemic metabolism. Then, high-coverage targeted lipidomics approach with multiple reaction monitoring (MRM) was utilized to provide extensive detection of lipid metabolites in VAT and SAT. RESULTS: CL316,243 notably ameliorated the systemic metabolism and induced brown remodeling of SAT but browning resistance of VAT. Comprehensive lipidomics analysis revealed browning heterogeneity of VAT and SAT with more dramatic alteration of lipid classes and species in VAT rather than SAT, though VAT is resistant to browning. Adrenergic stimulation differentially affected glycerides content in VAT and SAT and boosted the abundance of more glycerophospholipids species in VAT than in SAT. Besides, CL316,243 increased sphingolipids in VAT without changes in SAT, meanwhile, elevated cardiolipin species more prominently in VAT than in SAT. CONCLUSIONS: We demonstrated the browning heterogeneity of WAT and identified potential lipid biomarkers which may provide lipid targets for overcoming VAT browning resistance.
Asunto(s)
Tejido Adiposo Blanco/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Dioxoles/farmacocinética , Lipidómica , Receptores Adrenérgicos beta 3/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
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.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Insuficiencia Renal/metabolismo , Tiazoles/farmacocinética , Acetanilidas/sangre , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangre , Adulto , Anciano , Envejecimiento/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores del Citocromo P-450 CYP2D6/sangre , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/sangre , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Desipramina/sangre , Desipramina/farmacocinética , Interacciones Farmacológicas , Femenino , Gemfibrozilo/sangre , Gemfibrozilo/farmacocinética , Glucuronosiltransferasa/metabolismo , Humanos , Itraconazol/sangre , Itraconazol/farmacocinética , Lorazepam/sangre , Lorazepam/farmacocinética , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Tiazoles/sangre , Adulto Joven , Zidovudina/sangre , Zidovudina/farmacocinéticaRESUMEN
Mirabegron is a kind of ß3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3â379.6, m/z 326.4â121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Tiazoles/farmacocinética , Acetanilidas/administración & dosificación , Acetanilidas/sangre , Administración Intravenosa , Administración Oral , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/sangre , Animales , Cromatografía Líquida de Alta Presión , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem , Tiazoles/administración & dosificación , Tiazoles/sangreRESUMEN
SUMMARY Mirabegron is a kind of β3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3→379.6, m/z 326.4→121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.
RESUMO Mirabegron é um tipo de agonista do receptor adrenérgico beta 3 que demonstra eficácia no tratamento de bexiga hiperativa. Nesta pesquisa, o método UPLC-MS/MS é desenvolvido e validado para o estudo da farmacocinética mirabegron em ratos. Um método de precipitação de proteínas é aplicado para a preparação de amostras com acetonitrilo. 397.3 → 379.6 M / Z, M / Z 326.4 → 121.0 para mirabegron, tolterodina (IS), respectivamente, para o íon positivo foi realizado para quantificação. O método é fiável e reprodutível em nosso estudo (precisão intradia ≤ 11,06%; precisão entredia ≤ 11.43%), com curvas de concentração linear de 5 a 2 ng/ml (R2 > 0,999). Estudos de estabilidade demonstraram que mirabegron permanece estável sob uma variedade de condições de armazenamento. Este método foi aplicado com sucesso para a determinação de mirabegron em ratos após administração oral e intravenosa.
Asunto(s)
Animales , Masculino , Ratas , Tiazoles/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Acetanilidas/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/sangre , Administración Oral , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/sangre , Administración Intravenosa , Acetanilidas/administración & dosificación , Acetanilidas/sangreRESUMEN
Mirabegron is a relatively new drug introduced to treat overactive bladder syndrome. It can be used either on its own or as part of a combination. This drug has been extensively studied, with a good number of Phase II and Phase III trials showing promising outcomes. These studies show that mirabegron is an effective, well-tolerated drug, which could have some adverse effects of concern. In this review, we look at the trials on mirabegron, as well as its pharmacokinetics, mechanism of action, and side effects as documented in the literature.
Asunto(s)
Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/efectos adversos , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Humanos , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
BACKGROUND AND OBJECTIVES: Mirabeg ron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC). METHODS: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo. Twenty-four male and female subjects received single doses of warfarin (25 mg) alone and in combination with mirabegron (100 mg once daily). Twenty-five male and female subjects were administered digoxin (0.25 mg) alone and in combination with mirabegron (100 mg once daily). Thirty female subjects received low-dose COC containing ethinylestradiol (EE)/levonorgestrel (LNG) (30/150 µg once daily) in combination with mirabegron (100 mg once daily) or placebo. Pharmacokinetic parameters were determined by non-compartmental methods. Absence of a Pharmacokinetic interaction was concluded if the 90 % confidence intervals (CI) of geometric least-squares means ratio of area under the curve (AUC) and maximum concentration (C max) were contained within the standard 80-125 % no-effect boundaries. The effect of mirabegron on warfarin International Normalized Ratio (INR) was also assessed. RESULTS: Mirabegron increased digoxin AUC and Cmax by 27 and 29 %, respectively, indicating that mirabegron is a weak inhibitor of P-glycoprotein (P-gp) in vivo. Co-administration of mirabegron did not affect the pharmacokinetics of metformin, warfarin, EE and LNG, or warfarin INR, except for a slight extension of the 90 % CI for the C max ratio for metformin (lower limit 79 %). Metformin decreased mirabegron AUC and C max by 21 %. Most treatment-emergent adverse events were mild, and all resolved by study end. CONCLUSIONS: No dose adjustment of either drug is required when mirabegron is administered concomitantly with metformin, warfarin or COC. Patients receiving mirabegron with digoxin may require additional monitoring of digoxin concentrations with dose adjustments where necessary, due to its narrow therapeutic index.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Anticonceptivos Orales Combinados/farmacocinética , Digoxina/farmacocinética , Interacciones Farmacológicas/fisiología , Metformina/farmacocinética , Tiazoles/farmacocinética , Warfarina/farmacocinética , Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Adulto , Área Bajo la Curva , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológicoRESUMEN
Mirabegron, the first selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1-7 and co-administered with mirabegron 50 mg from Days 8-14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmax and AUC24h of the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.
Asunto(s)
Acetanilidas/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Tiazoles/farmacología , Tartrato de Tolterodina/farmacocinética , Agentes Urológicos/farmacocinética , Acetanilidas/efectos adversos , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Compuestos de Bencidrilo/farmacocinética , Cresoles/farmacocinética , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Posmenopausia , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Tartrato de Tolterodina/efectos adversos , Agentes Urológicos/efectos adversos , Agentes Urológicos/farmacologíaRESUMEN
We evaluated the effects of probenecid, a potent organic anion transporter 1 (OAT1) and OAT3 inhibitor, on the pharmacokinetics and safety of ritobegron, a selective ß3 -adrenoceptor agonist, in healthy men. Twelve healthy men were administered a single oral dose of ritobegron (20 mg) alone or in combination with probenecid 2 hours before administration of ritobegron. In the combination sequence, additional doses of probenecid were administered 4 and 10 hours after the administration of ritobegron. Probenecid increased the Cmax of KUC-7322, an active form of ritobegron, and the AUC0-48 h by 1.39 and 2.93 times, respectively. Probenecid prolonged the t1/2 of KUC-7322 from 1.6 to 3.4 hours and decreased the renal clearance and cumulative fraction of KUC-7322 excreted in urine from 18.5 to 4.9 L/h and from 64.7% to 49.7%, respectively. Coadministration of probenecid did not influence adverse events, blood pressure, pulse rate, or heart rate relative to ritobegron alone. Although probenecid inhibited renal tubule secretion of KUC-7322 via OAT3 and increased KUC-7322 exposure, it did not influence adverse effects or vital signs. Therefore, clinically significant drug-drug interactions are unlikely to occur when probenecid is administered in combination with OAT3 inhibitors or substrates.
Asunto(s)
Acetatos/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Probenecid/farmacología , p-Hidroxianfetamina/análogos & derivados , Acetatos/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Adulto , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Semivida , Humanos , Masculino , Proteína 1 de Transporte de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Adulto Joven , p-Hidroxianfetamina/efectos adversos , p-Hidroxianfetamina/farmacocinéticaRESUMEN
The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Pirimidinonas/uso terapéutico , Pirrolidinas/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/toxicidad , Animales , Células CHO , Cricetinae , Cricetulus , Descubrimiento de Drogas , Femenino , Humanos , Lipidosis/inducido químicamente , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Pirimidinonas/farmacocinética , Pirimidinonas/toxicidad , Pirrolidinas/farmacocinética , Pirrolidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/efectos de los fármacos , Receptores Adrenérgicos beta/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacos , Difracción de Rayos XRESUMEN
Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.
Asunto(s)
Acetatos/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Proteínas Portadoras/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , p-Hidroxianfetamina/análogos & derivados , Acetatos/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Proteínas Portadoras/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Perros , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Técnicas In Vitro , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Ratas , Especificidad de la Especie , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/enzimología , Fracciones Subcelulares/metabolismo , p-Hidroxianfetamina/farmacocinética , p-Hidroxianfetamina/farmacologíaRESUMEN
PURPOSE: The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a ß3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. METHODS: In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. FINDINGS: After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. IMPLICATIONS: 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.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Tiazoles/farmacocinética , Vejiga Urinaria Hiperactiva/metabolismo , Agentes Urológicos/farmacocinética , Acetanilidas/efectos adversos , Acetanilidas/uso terapéutico , Administración Oral , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Adulto , Área Bajo la Curva , Pueblo Asiatico/estadística & datos numéricos , Ingestión de Alimentos/fisiología , Ayuno/metabolismo , Femenino , Voluntarios Sanos , Humanos , Masculino , Factores Sexuales , Tiazoles/efectos adversos , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/etnología , Agentes Urológicos/efectos adversos , Agentes Urológicos/uso terapéutico , Adulto JovenRESUMEN
INTRODUCTION: Overactive bladder (OAB) and urinary incontinence, although not life-threatening, are very bothersome chronic health conditions. The limitations of current pharmacological treatment urge the need for novel drugs with alternative mechanisms of action. Huge efforts in this area of research led to the synthesis of several selective and potent ß3-adrenoceptor agonists that gained relevance through research during the late 80s and 90s. Mirabegron was the first compound of this new class of drugs that showed preclinical efficacy in several models of storage bladder dysfunction, together with a favorable human pharmacological profile. Having passed the proof-of-concept stage, an extensive clinical development and pharmacology program was performed during the last 10 years, involving >10,000 individuals, before mirabegron was granted marketing approval. AREAS COVERED: In this case history, the authors review the milestones in mirabegron's discovery based on a systematic literature review. EXPERT OPINION: Thanks to its tolerability and safety/efficacy balance, mirabegron has potential to fill a need for new treatment options for OAB, and paves the way for further development of a completely new class of drugs aimed to treat this condition. However, the exact role of mirabegron in clinical practice has yet to be defined. Further studies are needed in order to clarify, together with post-launch information, critical safety issues and cost-effectiveness in head-to-head comparison with current standard treatments.
Asunto(s)
Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Incontinencia Urinaria/tratamiento farmacológico , Agentes Urológicos/uso terapéutico , Acetanilidas/efectos adversos , Acetanilidas/química , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/efectos adversos , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Animales , Humanos , Receptores Adrenérgicos beta 3/metabolismo , Tiazoles/efectos adversos , Tiazoles/química , Tiazoles/farmacocinética , Sistema Urinario/metabolismo , Agentes Urológicos/efectos adversos , Agentes Urológicos/química , Agentes Urológicos/farmacocinéticaRESUMEN
INTRODUCTION AND HYPOTHESIS: Mirabegron is a novel ß3-adrenoceptor agonist recently approved by Japanese, American, and European authorities for overactive bladder (OAB) therapy. Here we review existing knowledge on this new class of medication, analyze existing literature on the topic, and make recommendations regarding its administration and necessary future studies. METHODS: We reviewed the current literature and analyzed mirabegron efficacy, safety, and suitability for treating OAB symptoms. We performed a systematic search of Medline/PubMed, and Embase. Studies exploring mechanisms involved in the effects of mirabegron were included. Searches were limited to the English language. RESULTS: Two phase II and two large-scale phase III multinational randomized controlled trials have supported mirabegron efficacy and tolerability with up to 12 weeks of therapy in OAB patients. The reported frequency and severity of treatment-emergent and serious adverse events were similar to antimuscarinics but with more than threefold lower incidence of dry mouth than with tolterodine. However, effects on the cardiovascular system, cognitive functions, pharmacokinetic interactions with other drugs, and long-term adverse events have not yet been fully investigated. CONCLUSION: Anticholinergic drugs should remain the first-line pharmacologic treatment for OAB until head-to-head comparative study eventually shows that mirabegron has equivalent or superior efficacy. However, it seems logical to use mirabegron as second-line treatment of OAB in patients who are poor responders or intolerant to anticholinergics.
Asunto(s)
Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Tiazoles/uso terapéutico , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Antagonistas Muscarínicos/uso terapéutico , Tiazoles/farmacocinética , Resultado del TratamientoRESUMEN
Inflammation reduces pharmacological response to ß1-blockers by down-regulating the target receptor protein. This may contribute to the sub-optimal response to pharmacotherapy with ß-blockers. Nebivolol is a third generation ß-adrenoceptor (AR) blocker with high selectivity for blocking ß1 and ß3-agonistic properties. We studied whether response to nebivolol is also reduced by inflammation. Male Sprague-Dawley rats (Inflamed; Mycobacterium butyricum induced) and Control (healthy) were orally administered single doses of 2 mg/kg nebivolol (n=5) or 25 mg/kg propranolol (positive control, n=7-8); ECG recorded for PR and RR interval measurements; serial blood samples were collected for pharmacokinetic assessment. Subsequently, the myocardial ß1, ß2 and ß3-AR levels were measured in homogenized hearts. For propranolol, inflammation resulted in increased concentration but reduced response and down-regulation of ß1- AR. The action and disposition of nebivolol were, however, unaffected by inflammation despite the reduced ß1-AR levels. The levels of ß2 and ß3-AR were unaffected by inflammation. The consistency of response to nebivolol despite inflammation may be due to the predominance of contribution of ß2 and ß3-AR. The lack of an inhibitory effect of inflammation on the clearance of nebivolol is suggestive of mechanisms other than an efficient hepatic metabolism for its low bioavailability. If extrapolated to human, nebivolol may be a more effective cardiovascular drug when inflammatory conditions are present.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3/farmacología , Benzopiranos/farmacología , Etanolaminas/farmacología , Inflamación/fisiopatología , Propranolol/farmacología , Administración Oral , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/farmacología , Animales , Benzopiranos/farmacocinética , Electrocardiografía , Etanolaminas/farmacocinética , Humanos , Masculino , Miocardio/metabolismo , Nebivolol , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 1/efectos de los fármacos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/efectos de los fármacos , Receptores Adrenérgicos beta 3/metabolismo , Especificidad de la EspecieRESUMEN
The pharmacokinetic profile of ritobegron, a novel, selective ß3-adrenoceptor agonist, was investigated in rats. Ritobegron, an ethyl ester prodrug of the active compound KUC-7322, or KUC-7322 itself was orally administered (10 mg/kg). Ethyl esterification resulted in a 10-fold increase in the area under the plasma concentration-time curve (AUC(0-t)), as compared to KUC-7322. Following intravenous administration of KUC-7322 (1 mg/kg), total blood clearance was 1.36 L/h/kg, suggesting that intrinsic hepatic clearance is the rate-limiting step in KUC-7322 excretion. When ritobegron was orally administered (0.3, 1, 3, and 10 mg/kg), plasma concentrations of KUC-7322 rapidly increased and reached a maximum concentration (C(max)) at 0.25 to 0.31 h. KUC-7322 levels rapidly decreased, with a half-life (t 1/2) of 0.42 to 1.37 h thereafter. AUC(0-t) did not show a dose-dependent increase. The bioavailability of KUC-7322 was estimated to be 4%. Following oral administration of [14C]ritobegron (3 mg/kg), radioactivity concentrations in tissues rapidly increased and declined in parallel with changes in plasma concentration. In most of tissues, excluding the liver, kidney, urinary bladder, stomach and small intestine, radioactivity concentrations were lower than that in plasma. In plasma, bile, urine, and feces, KUC-7322 and its glucuronide, sulfate, and glutathione conjugates were detected. The glucuronide conjugate of KUC-7322 was the predominant metabolite in bile, plasma, and urine, and KUC-7322 was predominant in feces. Ritobegron was not detected in any of the samples. The cumulative excretion of radioactivity in urine and feces were 28.7% and 68.3% of the dose, respectively, up to 120 h after administration.
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Acetatos/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , p-Hidroxianfetamina/análogos & derivados , Acetatos/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/metabolismo , Animales , Área Bajo la Curva , Bilis/metabolismo , Biotransformación , Heces/química , Técnicas In Vitro , Absorción Intestinal , Masculino , Unión Proteica , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , p-Hidroxianfetamina/metabolismo , p-Hidroxianfetamina/farmacocinéticaRESUMEN
Mirabegron, a weak-basic compound, is a potent and selective ß3-adrenoceptor agonist for the treatment of overactive bladder. Mirabegron extended release formulation shows dose-dependent oral bioavailability in humans, which is likely attributable to saturation of intestinal efflux abilities leading to higher absorption with higher doses. This study evaluated the membrane permeability of mirabegron and investigated the involvement of human intestinal transport proteins in the membrane permeation of mirabegron. Transcellular transport and cellular/vesicular uptake assays were performed using Caco-2 cells and/or human intestinal efflux (P-glycoprotein [P-gp], breast cancer resistance protein [BCRP], and multidrug resistance associated protein 2 [MRP2]) and influx (peptide transporter 1 [PEPT1], OATP1A2, and OATP2B1) transporter-expressing cells, vesicles, or Xenopus laevis oocytes. The absorptive permeability coefficients of mirabegron in Caco-2 cells (1.68-1.83 × 10(-6) cm/s) at the apical and basal pH of 6.5 and 7.4, respectively, were slightly higher than those of nadolol (0.97-1.41 × 10(-6) cm/s), a low permeability reference standard, but lower than those of metoprolol and propranolol (both ranged from 8.49 to 11.6 × 10(-6) cm/s), low/high permeability boundary reference standards. Increasing buffer pH at the apical side from 5.5 to 8.0 gradually increased the absorptive permeation of mirabegron from 0.226 to 1.66 × 10(-6) cm/s, but was still less than the value in the opposite direction (11.0-14.2 × 10(-6) cm/s). The time- and concentration-dependent transport of mirabegron was observed in P-gp-expressing cells and OATP1A2-expressing oocytes with apparent Km values of 294 and 8.59 µM, respectively. In contrast, no clear BCRP-, MRP2-, PEPT1-, or OATP2B1-mediated uptake of mirabegron was observed in their expressing vesicles or cells. These findings suggest that mirabegron has low-to-moderate membrane permeability and P-gp is likely to be involved in its efflux into the lumen in the intestinal absorption process. The results also suggest that mirabegron could possibly be transported by intestinal influx transporters as well as simple diffusion.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Tiazoles/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico Activo , Células CACO-2 , Permeabilidad de la Membrana Celular , Femenino , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Absorción Intestinal/fisiología , Células LLC-PK1 , Proteínas de Neoplasias/metabolismo , Oocitos/metabolismo , Transportadores de Anión Orgánico/metabolismo , Transportador de Péptidos 1 , Proteínas Recombinantes/metabolismo , Porcinos , Simportadores/metabolismo , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Xenopus laevisRESUMEN
BACKGROUND: Mirabegron is a ß3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. OBJECTIVE: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. METHODS: Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. RESULTS: Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. CONCLUSIONS: Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Tiazoles/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Cetoconazol/farmacología , Masculino , Persona de Mediana Edad , Rifampin/farmacología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Mirabegron, a selective ß3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated. METHODS: Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites. RESULTS: Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects. CONCLUSION: Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.