Purpo: To discuss the pharmacotherapeutic aspects of Mirabegron which is a first-in-class novel β3 receptor agonist drug recently approved by the food and drug administra-tion (FDA) for the treatment of overactive bladder (OAB).
歌唱活动教案
Materials and Methods: We conducted a computerized arch of the MEDLINE/PUB-MED databas with the word Mirabegron, β3 receptor agonist and overactive bladder. Results: Effect of Mirabegron on β3 adrenergic receptor purportedly releas nitric ox-ide (NO) by an increa in intracellular Ca 2+ through accumulation of cyclic adenosine monophosphate (cAMP). Along with NO which relaxes the detrusor muscle, it also releas an urothelial-derived inhibiting factor (UDIF) that inhibits contractions. It in-creas the bladder capacity by causing bladder relaxation during the storage pha.Conclusion: Mirabegron appears to be a promising treatment in OAB patients by shift-ing its management from reducing detrusor over-activity to inducing relaxation. Also it lacks the troublesome side effects associated with the standard antimuscarinic manage-ment.
Keywords: mirabegron; β3 receptor agonist; urinary bladder; overactive; drug therapy
1Department of Pharmacology, Hamdard
Institute of Medical Sciences and Rearch and Associated Hakeem Abdul Hameed Centenary Hospit
al, Jamia Hamdard, New Delhi -110062, India
2Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi -110062, India
3Department of Physiology, Hamdard Institute of Medical Sciences and Rearch and Associated Hakeem Abdul Hameed Centenary Hospital, Jamia Hamdard, New Delhi -110062, India Mohammed Imran,1 Abul Kalam Najmi,2 Shams Tabrez 3
REVIEW
Mirabegron for Overactive Bladder:
A Novel, First-in-Class β3- Agonist Therapy
Corresponding Author:
Mohammed Imran, MD
Assistant Professor, Department of Pharma-cology, Hamdard Institute of Medical Sci-ences and Rearch and Associated Hakeem Abdul Hameed Centenary Hospital, Jamia Hamdard, New Delhi-
110062, India.Tel: +91 954 007 5851 E mail: drimran@aol.in Received September 2012Accepted November 2012
杜甫简介资料INTRODUCTION
物理学家英语O veractive bladder (OAB) includes constellation
of symptoms such as urinary urgency, urge uri-
nary incontinence, nocturia and frequency. Ur-gency is the hallmark of OAB. Patients may describe it as a sudden compelling desire to urinate that is difficult to defer. While urinary frequency is defined as voiding more than eight times in a 24-hour period, Nocturia is defined as the need to wake up one or more times per night for urination.(1)
Urinary bladder physiology
Normal bladder stores urine when the sympathetic nervous system (SNS) relaxes the detrusor muscle and clos the sphincters at the bladder outlet. It also inhibits the parasym-pathetic nervous system (PNS). When it attains a volume of around 200-400 ml, signal moves from the peripheral nerv-ous system including autonomic, somatic and nsory affer-ent innervations to the central nerv
ous system resulting in a nsation of urge. Normal urination begins after the relea of acetylcholine (Ach) from the PNS and thereby contrac-tion of the detrusor muscle. At the same time SNS opens the internal sphincter and somatic nervous system opens the external sphincter. Multiple outgoing and incoming neural pathways and neurotransmitters are involved in urine stor-age and voiding process.(2,3)
Pathophysiology of OAB
OAB has multifactorial etio-pathogenesis. Caus of the detrusor muscle overactivity may be neurogenic, myogenic, or idiopathic in origin. Any of the may result in a constel-lation of urinary symptoms associated with OAB. Incread contraction in overactive bladders is due to hypernsitivity to cholinergic agonists through muscarinic (M2 or M3) re-ceptors. Acetylcholine relead from PNS caus activation of M3 receptors which is responsible for bladder contrac-tion. It caus ri in cytosolic calcium (Ca2+) from intracel-lular sarcoplasmic reticulum stores through activation of G-protein coupled receptor (GPCR) mediated phospholipa C breakdown. Generation of Inositol triphosphate (IP3) triggers Ca2+relea. M2 receptor activation converly caus a fall in cyclic adenosine monophosphate (cAMP) preventing relaxation.(4)
Antimuscarinic drug management Antimuscarinic drugs antagonize the effects of acetylcho-line on muscarinic receptors. They reduce the contractions of the detrusor smooth muscle of the bladder and thus re-duce the intensity of urge symptoms. Becau of the as-sociated troublesome anticholinergic side effects, newer antimuscarinics have been discovered to lectively target M3 receptors to reduce the side effects and increa the ef-ficacy. But they still have limitations of producing adver events.(5) Therefore, now, there would be a shift in manage-ment from reducing over activity to producing relaxation of the urinary bladder.
Mirabegron – a novel β3 agonist
The FDA, recently in June 2012, has approved a drug called Mirabegron in USA which had earlier been approved in Ja-pan in 2011. The prent review was conducted to have a ra-tionale, pharmacotherapeutic and comprehensive informa-tion of this new class of drug for the management of OAB.
MATERIALS AND METHODS
We arched the MEDLINE/PUBMED databas of the National Library of Medicine for the comprehensive in-formation on the newly introduced mirabegron therapy for OAB. The terms ud f
or the arch included mirabegron, β3 receptor agonist, overactive bladder and the combina-tions of the terminologies. All the relevant information obtained from other than PubMed/Medline arch was also incorporated.
RESULTS
Mirabegron
It is first-in-class lective β3 adrenergic receptor agonist. It is indicated for treatment of OAB in 25 mg extended relea once daily starting do and may be progresd
to once daily 50 mg recommended do.(6) Activation of β3-adrenoceptors (β3-ARs) by mirabegron increas blad-der capacity by causing bladder relaxation as induced by sympathetic nerve activation especially during the storage pha of the fill-void cycle.(7)
Mechanism of Action
It has been demonstrated in rat experiments that activation of β3-AR by isoproterenol in urothelial cells can relea ni-tric oxide (NO) by increasing the intracellular Ca2+ through cAMP accumulation. Activation of β3-AR not only caus relaxation by releas NO but also inhibits detrusor mus-cle con
traction by releasing an urothelial derived inhibiting factor (UDIF). This implies that β3-AR agonists helps blad-der storing capacity through direct inhibition of the detrusor as well as inhibition of the bladder afferent neurotransduc-tion.(8,9)
Pharmacokinetics
The starting dosage of Mirabegron is 25 mg once daily with or without food. It reaches a bioavailability of 29% at a do of 25 mg which further increas to 35% at a do of 50 mg. It is extensively distributed in the body with a volume of distribution (aVd) of approximately 1670 L. It is moder-ately bound to the plasma protein (71%) with equal affinity to the albumin and alpha-1-acid glycoproteins. It attains a 2 fold higher concentration in red blood cells than in plasma.
(10) There is a difference between linearity of intravenous and oral pharmacokinetics parameters. The drug concentra-tion after i.v. dosing shows the linearity in the range of 7.5 – 50 mg, however there is incread bioavailability through oral route as the do increas from 29% for 25 mg to 45% at 150 mg.(11)
Multiple enzymatic pathways are involved in mirabegron metabolism involving dealkylation, oxidation, and glucu-ronidation and amide hydrolyis. Although CYP3A4 and CYP2D6 isoenzymes m
etaboli this drug their role is lim-ited in overall elimination. Other than the isoenzymes, its metabolism may also involve butyrylcholinestera, uridine diphospho-glucuronosyltransferas and alcohol dehydro-gena. Two major pharmacologically inactive metabolites were detected in human plasma and the reprent 16% and 11% of the total exposure. Approximately 25% of it is excreted unchanged in the urine and there is no excretion in the feces with a terminal half-life of approximately 50 hours. Renal clearance is mainly do dependent due to tu-bular cretion and glomerular filtration and it (CLR) is ap-proximately 13 L/h.(7) There is no apparent age difference in the pharmacokinetics parameters but women show ap-prox. 40% higher Cmax (Maximum Concentration reached) and AUC (Area Under the Curve) than men and approx. 20% higher even after the weight correction.(12)
派遣证明It is effective within 8 weeks in dos of 25 mg and 4 weeks in dos of 50 mg respectively after its administration as once a do. Therefore do may be incread to 50 mg once daily after asssing individual patient efficacy and tolerability. It has been advid in prescribing information to take it with water, swallowed whole and should not be chewed, divided, or crushed. It has been cautioned not to exceed beyond 25mg once daily in patients with vere renal impairment and patients with moderate hepatic im-pairment (Child-Pugh Class B). It is not recommended for u in p
atients with end stage renal dia (ESRD), or in patients with vere hepatic impairment (Child-Pugh Class C). It is supplied in two different strengths of 25 mg as well as 50 mg extended-relea tablets.(13)
It has been approved with certain precautions and warnings that should be exercid while prescribing. Periodic moni-toring of blood pressure is recommended as it can increa blood pressure especially in hypertensive patients. Al-though it is not recommended for u in vere uncontrolled hypertensive patients but randomized placebo-controlled studies (data submitted for its approval) show do depend-ent increa in supine blood pressure in healthy volunteers. Approximately mean maximum systolic/diastolic blood pressure increa was 3.5/1.5 mmHg over the placebo in healthy volunteers as compared to the 0.5 – 1 mmHg in-crea over placebo in OAB patients. There is also a risk of
Mirabegron for Overactive Bladder | Imran et al
urinary retention in patients with bladder outlet obstruction and in patients taking anticholinergic drugs for OAB.(7)
Interactions
解方程式
It is a moderate inhibitor of CYP2D6. It can increa me-toprolol and desipramine concentration. Appropriate moni-toring is recommended and do adjustment may be nec-essary for narrow therapeutic index CYP2D6 substrates such as thioridazine, flecainide, propafenone and digoxin. Despite the limitations in prescribing information, how-ever, there is no contraindication associated with this drug.
(14) It has also shown to interact with warfarin by increasing the Cmax by approximately 4% and AUC by 9% after the multiple dos of 100mg, however there is no effect follow-ing a single do administration of 25 mg on the warfarin pharmacodynamics endpoints such as International Nor-malized Ratio (INR) and prothrombin time. A cautious u is advid along with the warfarin intake.(7)
Adver effects
The data from four clinical trial studies mentioned in pre-scribing information relead by FDA were ud to evaluate the safety and efficacy of Mirabegron in OAB patients.(7) The studies 1, 2 and 3 were done for a period of 12 weeks as double–blind, placebo controlled in 2736 patients includ-ing 432 patients on 25 mg, 1375 on 50 mg and 929 on 100 mg strength once daily. Study 4 was done to
evaluate safety over a period of 1 year as randomized, fixed do, double blind, active–controlled in 1632 patients including 812 pa-tients on 50 mg and 820 patients on 100 mg strength. Out of the 1632 patients in study 4 only 564 patients completed the study for full one year. The most frequent (0.2%) adver events in three (Study 1, 2 and 3) 12 weeks studies that led to the discontinuation of the drugs in clinical studies were naua, headache, hypertension, diarrhea, constipation, diz-ziness and tachycardia. The rious adver events associ-ated with the studies were atrial fibrillation (0.2%) and prostate cancer (0.1%) found in more than one patient and at a rate greater than placebo. While study 4 was discontin-ued by the participants due to adver events such as con-stipation (0.9%), headache (0.6%), dizziness (0.5%), hy-pertension (0.5%), dry eye (0.4%), naua (0.4%), blurred vision (0.4%) and urinary tract infection (0.4%) which were reported in more than 2 patients and at a rate greater than active control, the rious adver events in this study in-cluded cerebrovascular accidents (0.4%) and osteoarthritis (0.2%). In addition, a few cas of malignancies like breast cancer, lung neoplasm and prostate cancer were reported in more than two patients taking 100 mg do of Mirabe-gron. The rate of neoplasm in patients taking Mirabegron 50 mg, Mirabegron 100 mg and active control once daily were 0.1%, 1.5% and 0.5% respectively in study 4.(7)
上诉不加刑原则In general, there are some adver reactions reported which demand caution in u of this therapy. The most common adver reactions (i.e., in greater than 2% of patients) were hypertension, nasopharyngitis, urinary tract infection and headache. Other adver events exceeding placebo rate and reported by 1% or more patients are hypertension, na-sopharyngitis, urinary tract infection, headache, constipa-tion, upper respiratory tract, infection, arthralgia, diarrhea, tachycardia, abdominal pain and fatigue. Tho side effects developing in less than 1% of patients include palpitations, incread blood pressure, glaucoma, dyspepsia, gastritis, abdominal distension, sinusitis, rhinitis, incread GGT, incread AST, incread ALT, incread LDH, nephrolithi-asis, bladder pain, vulvovaginal pruritus, vaginal infection, urticaria, leukocytoclastic vasculitis, rash, pruritus, purpu-ra, lip edema (7)
The approval of Mirabegron was bad on three placebo-controlled pha 3 studies in which 12 weeks treatment from 25 mg and 50 mg do resulted in statistically signifi-cant improvement in co-primary efficacy endpoints. That is the change from baline to the end of the treatment after 12 weeks in respect of mean number of incontinence epi-sodes per 24 hours and mean number of micturition per 24 hours bad on a 3 day micturition diary. Mirabegron in 25 mg strength reduced incontinence episodes by 1.36 from a baline of 2.65 with a significant difference of 0.40 versus
placebo in 12 weeks (P-value=0.005). The micturition epi-sodes reduced by 1.65 from a baline of 11.68 with a sig-nificant difference of 0.47 versus placebo (P = .007). While 50 mg strength reduced the incontinence episodes by 1.38 from a baline of 2.51 with a significant difference of 0.42 (P = .001). The micturition episodes reduced by 1.60 from a baline of 11.66 with a difference of 0.42 versus placebo (P= .015).(7)
Although antimuscarinic drugs are the standard treatment in OAB management but their adver effects and declining efficacy leads to long term compliance issues. Mirabegron is a new class of drug acting through dual mechanism of in-hibiting afferents and causing relaxation of detrusor muscle. One of the animal studies compared the effects of Oxybu-tynin with the Mirabegron on single unit afferents activities of Aδ-fibers and C-fibers in respon to the bladder filling. It was found to be superior in inhibiting the afferents and suppressing the micro contractions of urinary bladder.(15) Limitations
The safety and efficacy studies have not been conducted in pediatrics patients and u for pregnant ladies are only advid after individualizing the risk benefit asssment. However it is excreted in the human milk and therefore not recommended in nursing females while no do adjustment is required for geriatric patients.(10) CONCLUSION
This class of drugs have the great potential in shifting the management of the OAB through a different mechanism of action which has never tried earlier. Although Mirabegron has lower side effects as compared to the earlier drugs ud in the management of OAB but it has yet to be standardized in respect of the gender pharmacokinetics variations and a few specified populations. The drug is to be ud on an in-dividual basis till long term studies prove the safety of the drug for long term intake.
CONFLICT OF INTEREST
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