CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`213801Orig1s000
`
`CLINICAL PHARMACOLOGY
`REVIEW(S)
`
`
`
`
`
`
`

`

`Office of Clinical Pharmacology Review
`
`NDA or BLA Number
`Link to EDR
`
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`
`Dosage Form and Strength
`
`Route of Administration
`Proposed Indication
`
`Applicant
`Associated IND
`OCP Review Team
`
`OCP Final Signatory
`
`NDA 213801 and NDA 202611/S-017
`\\CDSESUB1\evsprod\NDA213801\0001
`\\CDSESUB1\evsprod\NDA202611\0017
`9/28/2020
`Priority
`MYRBETRIQ and MYRBETRIQ GRANULES
`Mirabegron extended-release
`tablets and mirabegron
`extended-release granules for oral suspension
`Tablets: 25 mg and 50 mg
`Granules for oral suspension: 8.3 g of granules containing
`830 mg mirabegron per bottle
`Oral
`Treatment of neurogenic detrusor overactivity (NDO) in
`pediatric patients aged 3 years and older
`Astellas Pharma Global Development, Inc.
`IND 069416
`Peng Zou, PhD; Yun Wang, PhD; Jingyu Yu, PhD; Yanhui
`Lu, PhD
`Yanhui Lu
`Team Leader
`Office of Clinical Pharmacology
`
`Reference ID: 4757121
`
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`Table of Contents
`
`1. EXECUTIVE SUMMARY .......................................................................................................................3
`1.1 Recommendations................................................................................................................................3
`1.2 Post-Marketing Requirements and Commitments ...............................................................................4
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT........................................................4
`2.1 Pharmacology and Clinical Pharmacokinetics.....................................................................................4
`2.2 Dosing and Therapeutic Individualization...........................................................................................6
`2.2.1 General dosing ..............................................................................................................................6
`2.2.2 Therapeutic individualization .......................................................................................................6
`2.3 Outstanding Issues ...............................................................................................................................6
`2.4 Summary of Labeling Recommendations............................................................................................6
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW...........................................................7
`3.1 Overview of the Product and Regulatory Background ........................................................................7
`3.2 General Pharmacology and Pharmacokinetic Characteristics .............................................................7
`3.3 Clinical Pharmacology Review Questions...........................................................................................9
`3.3.1 To what extent does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness? ...................................................................................................9
`3.3.2 Is the proposed dosing regimen appropriate for the general patient population for which the
`indication is being sought?.....................................................................................................................9
`3.3.3 Is an alternative dosing regimen and/or management strategy required for subpopulations based
`on intrinsic factors?..............................................................................................................................14
`3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate
`management strategy?..........................................................................................................................15
`3.3.5 Is the to-be-marketed formulation the same as the clinical trial formulation, and if not, are there
`bioequivalence data to support the to-be-marketed formulation .........................................................17
`4. APPENDICES .........................................................................................................................................17
`4.1 Summary of Bioanalytical Method Validation and Performance......................................................17
`4.2 Clinical BA/BE Assessments………………………………………………………………..……...18
`4.2.1 Study 178-CL-201……………………...……………………………………………………....19
`4.2.2 Study 178-CL-208……………………………………………………….………..………..…..21
`4.2.3 Study 178-CL-202 ……………………..…...………..………………………….…………..…23
`4.2.4 Study 178-CL-203..………………………..…...............................………..………………..…25
`4.3 Population PK Analyses.....................................................................................................................26
`4.4 Additional Analysis (Issue-based analysis) .......................................................................................37
`4.5 Exposure-Response Analyses ............................................................................................................46
`
`Reference ID: 4757121
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`1. EXECUTIVE SUMMARY
`Myrbetriq® (mirabegron, 25 mg and 50 mg extended-release tablets) is currently approved in the US for
`the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and
`urinary frequency in adults (NDA 202611) in 2012. In the NDA approval letter dated June 28, 2012, to
`satisfy the Pediatric Research Equity Act (PREA) requirements, FDA requested the Applicant Astellas
`Pharma Global Development, Inc. (Astellas) to develop mirabegron ER microgranule-based suspension in
`children from 5 to < 18 years of age with neurogenic detrusor overactivity (NDO) as a postmarketing
`requirement (PMR). FDA requested two PMR studies:
`
`
`
`
`
`PMR 1898-1: Open label, multicenter single ascending dose study to evaluate pharmacokinetics,
`safety and tolerability of mirabegron modified release microgranule based suspension in children
`from 5 to < 18 years of age with NDO or OAB (178-CL-202 and 178-CL-203).
`PMR 1898-2 Open label, baseline-controlled, multi-center, sequential dose titration study
`followed by a fixed dose observation period to evaluate pharmacokinetics, safety and efficacy of
`mirabegron modified release microgranule-based suspension in children from 5 to < 18 years of
`age with NDO (178-CL-206/206A).
`
`On March 18, 2016, FDA issued a written request thereby lowering the minimum age in the pediatric
`population from 5 years to 3 years for the pivotal phase 3 study 178-CL-206A.
`
`The final reports for Studies 178-CL-202 and 178-CL-203 were submitted to IND 069416 on February
`24, 2016 and March 31, 2017, respectively. The applicant received the fulfillment of PMR 1898-1 letter
`on December 27, 2018. NDA 213801 and concurrent efficacy supplement-17 (S-17) to NDA 202611
`were filed on September 28, 2020 to fulfill the PMR 1898-2 and to satisfy the written request dated
`March 18, 2016. The proposed indication in current submission is for the treatment of pediatric patients
`aged 3 to < 18 years with NDO. In addition to the approved Myrbetriq® extended-release (ER) tablets,
`Astellas has developed mirabegron ER granules (mirabegron for oral suspension) for pediatric patients.
`1.1 Recommendations
`The Office of Clinical Pharmacology Division of Cardiometabolic and Endocrine Pharmacology and
`Division of Pharmacometrics have reviewed the information contained in NDA 213801 and NDA
`202611/S-017 recommend approval of this NDA. The information also satisfies the PREA requirements
`1898-1 and 1898-2 outlined in the approval letter for NDA 202611 dated Jun 28, 2012 and the written
`requests issued on Mar 18, 2016.
`
`Key clinical pharmacology review issues with specific recommendations/comments are summarized in
`the table below:
`
`Review Issue
`Supportive evidence of
`effectiveness
`
`Recommendations and Comments
`Based on cross-study comparison, population pharmacokinetic
`(popPK) analysis showed that steady-state AUC0-t values of
`mirabegron for pediatric subjects receiving the proposed maximum
`dose (PED50, defined at the bottom of this table) fell within the
`range (42 – 854 ng*h/mL) of observed adult exposures receiving
`approved mirabegron tablets 50 mg once daily. Median steady-state
`AUC0-t values in children aged 3 to < 12 years (277 ng*h/mL) and
`adolescents aged 12 to < 18 years (260 ng*h/mL) receiving PED50
`were slightly higher than that in adults (188 ng*h/mL) receiving 50
`mg once daily. Similarly, steady-state AUC0-t values of mirabegron
`for pediatric subjects receiving the proposed starting dose (PED25,
`
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`General dosing instructions
`
`Dosing in patient subgroups
`(intrinsic and extrinsic factors)
`
`
`
`
`
`defined at the bottom of this table) fell within the range (17 – 578
`ng*h/mL) of observed adult exposures receiving approved
`mirabegron tablets 25 mg once daily.
`MYRBETRIQ Tablet or Granules should be taken with food in
`pediatric patients. The body weight-based doses are listed below:
`Patients with body weight ≥ 35 kg: tablets 25 - 50 mg once
`
`daily (QD); granules 48 – 80 mg QD
`Patients with body weight ≥ 22 kg and < 35 kg: granules 32
`– 64 mg QD
`Patients with body weight < 22 kg: granules 24 – 48 mg QD
`
`The daily dose of MYRBETRIQ Tablet or Granules should not
`exceed the recommended starting dose in the following populations:
`Pediatric patients with severe renal impairment (eGFR 15 to
`
`29 mL/min/1.73 m2).
`Pediatric patients with moderate hepatic impairment (Child-
`Pugh Class B).
`MYRBETRIQ Tablet or Granules is not recommended for use in
`pediatric patients with end-stage renal disease (ESRD) or in pediatric
`patients with severe hepatic impairment (Child-Pugh Class C). No
`dose adjustment is needed for pediatric patients with mild-to-
`moderate renal impairment and pediatric patients with mild hepatic
`impairment.
`Labeling
`Refer to Section 2.4 for the review team’s recommendations.
`Bridge between the to-be-
`To-be-marketed (TBM) formulations of mirabegron ER granules for
`marketed and clinical trial
`oral suspension and the approved mirabegron tablets were used in
`formulations
`the pivotal clinical trial (Study 178-CL-206A).
`Other (specify)
`None.
`PED50: pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the mirabegron 50 mg
`tablet once daily.
`1.2 Post-Marketing Requirements and Commitments
`None.
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`2.1 Pharmacology and Clinical Pharmacokinetics
`Mirabegron, also known as YM178, is an agonist of the human beta-3 adrenergic receptor (AR).
`Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-
`void cycle by activation of beta-3 AR which increases bladder capacity. For pediatric patients ≥ 35
`kg, the recommended starting dose is 25 mg once daily (QD) or 6 mL (8 mg/mL) QD with food, for
`mirabegron ER tablets and granules, respectively. The ER granules were reconstituted with water to
`prepare a suspension with a concentration of 8 mg/mL oral suspension. Based on individual patient
`efficacy and tolerability, the dose may be increased to 50 mg or 10 mL (i.e. 80 mg) once daily after 4-
`8 weeks for mirabegron ER tablets and oral suspension, respectively. For patients with body weight ≥
`22 kg and < 35 kg, the recommended starting dose and maximum doses are 4 mL and 8 mL of oral
`suspension QD, respectively, orally administered with food. For patients with body weight ≥ 11 kg
`and < 22 kg, the recommended starting dose and maximum doses are 3 mL and 6 mL of oral
`suspension QD, respectively, orally administered with food.
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`Absorption: Across different studies, the median Tmax of mirabegron following oral administration of a
`single dose of mirabegron ER tablets and oral suspension in pediatric patients under fed state was 4-5
`hours. Within the dosing range of 25 – 75 mg QD, pediatric patients receiving higher doses of mirabegron
`ER tablets showed greater extent of absorption compared to patients receiving lower doses of mirabegron
`ER tablets. In healthy adult subjects, the AUC0-inf, AUC0-t and Cmax of mirabegron oral suspension 50 mg
`administered under fed state were 56%, 63% and 82% lower than that of mirabegron ER tablet 50 mg
`administered under fed state. PopPK analysis showed that mirabegron oral suspension formulations had
`57.1% lower bioavailability (BA) compared to the tablet formulation in pediatric patients at the same
`dose.
`
`In healthy adult subjects, a high-fat meal decreased the AUC0-inf, AUC0-t and Cmax of mirabegron oral
`suspension by 45%, 49% and 63%, respectively. Similarly, in healthy adult subjects, a high-fat meal
`decreased the AUC0-inf, AUC0-t and Cmax of mirabegron ER tablets by 57%, 60% and 60%, respectively. In
`phase 3 study, mirabegron ER tablets or oral suspension were taken orally within 1 hour before or after
`breakfast. In drug label, both mirabegron ER tablets and oral suspension are proposed to be administered
`with food in pediatric NDO patients.
`
`Figure 1. Mean (+SD) Plasma Concentration-Time Profiles of Mirabegron Following Oral
`Administration of a Single Dose of (A) Mirabegron Oral Suspension 88 mg and (B) ER tablet 50 mg in
`Healthy Adult Subjects Under Fasted and Fed States
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`Source: Reviewer’s plots based on Applicant’s data from Studies 178-CL-201 and 178-CL-208
`
`Distribution: Mirabegron volume of distribution was relatively large in pediatric patients (the range of
`Vz/F under fed state across studies: 4895 – 13726 L) and increased with increasing body weight.
`
`Elimination: The terminal elimination half-life (T1/2) of mirabegron is approximately 26 to 31 hours in
`pediatric patients. PopPK model predicted that mirabegron clearance in pediatric patients increased with
`body weight.
`
`2.2 Dosing and Therapeutic Individualization
`
`2.2.1 General dosing
`MYRBETRIQ tablet and granules are not bioequivalent. For the two dosage forms, different body
`weight-based starting doses and maximum doses are proposed for pediatric patients.
`
` Pediatric patients weighing less than 35 kg: use MYBETRIQ granules only
`
`Maximum Dose (PED50)
`Starting Dose (PED25)
`Body Weight Range
`6 mL (48 mg) QD
`3 mL (24 mg) QD
`11 kg to less than 22 kg
`8 mL (64 mg) QD
`4 mL (32 mg) QD
`22 kg to less than 35 kg
`Note: PED25: pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the mirabegron 25
`mg tablet once daily; PED50: pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the
`mirabegron 50 mg tablet once daily.
`
`Pediatric patients weighing 35 kg or more: use MYBETRIQ tablets or MYBETRIQ granules
`For use of MYRBETRIQ tablets, the recommended starting dosage (PED25) is 25 mg QD orally. If
`needed, increase to a maximum dose (PED50) of MYRBETRIQ 50 mg QD orally. For use of
`MYRBETRIQ granules, the recommended starting dosage (PED25) is 6 mL (48 mg) QD orally. If
`needed, increase to a maximum dosage (PED50) of MYRBETRIQ granules 10 mL (80 mg) QD orally.
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`Both MYBETRIQ tablets and MYBETRIQ granules should be orally administered under fed state.
`
`2.2.2 Therapeutic individualization
`Renal Impairment: In pediatric phase 3 trial (Study 178-CL-206A), pediatric patients with mild-to-
`moderate renal impairment (eGFR < 90 mL/min and > 30 mL/min) were included and no dose adjustment
`was applied to these patients. Pediatric patients with severe renal impairment (eGFR < 30 mL/min) were
`excluded from Study 178-CL-206A. The clinical pharmacology review team does not recommend dose
`adjustment for pediatric patients with mild-to-moderate renal impairment. The team recommends that the
`dose for pediatric patients with severe renal impairment not exceed the recommended MYBETRIQ tablet
`or granule starting dose. MYBETRIQ tablets or MYBETRIQ granules have not been studied in patients
`with end-stage renal disease (ESRD) (CLcr less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2)
`or patients requiring hemodialysis. The use of MYBETRIQ tablets or MYBETRIQ granules in patients
`with ESRD or patients requiring hemodialysis is not recommended.
`
`Hepatic Impairment: In Study 178-CL-206A, pediatric patients with mild hepatic impairment were
`enrolled while pediatric patients with moderate-to-severe hepatic impairment were excluded. The clinical
`pharmacology review team does not recommend dose adjustment for pediatric patients with mild hepatic
`impairment. The team recommends that the dose for pediatric patients with moderate hepatic impairment
`not exceed the recommended MYBETRIQ tablet or granule starting dose. MYBETRIQ tablets or
`MYBETRIQ granules have not been studied in patients with severe hepatic impairment (Child-Pugh
`Class C). The use of MYBETRIQ tablets or MYBETRIQ granules in patients with severe hepatic
`impairment is not recommended.
`
`2.3 Outstanding Issues
`None.
`2.4 Summary of Labeling Recommendations
`The Office of Clinical Pharmacology has the following Labeling recommendation and comments:
`
`Section 2.5: proposed doses for pediatric patients with server renal impairment or moderate hepatic
`impairment.
`.
`Section 7.1: deleted
`Section 12.3: updated pharmacokinetic information for pediatric patients and MYBETRIQ granules.
`
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW
`
`3.1 Overview of the Product and Regulatory Background
`In addition to Myrbetriq® (mirabegron, 25 mg and 50 mg extended-release tablets) approved by the FDA
`under NDA 202611, Astellas has developed mirabegron granules (mirabegron for oral suspension) for
`pediatric indication. These granules form an oral suspension (8 mg/mL mirabegron) when reconstituted
`with water. In support of NDA 213801 and NDA 202611/S-17, Astellas conducted 5 clinical studies
`including four phase 1 studies (two relative bioavailability/food effect studies and two single ascending
`dose studies) and one phase 3 study. The clinical trials that support the safety and efficacy of
`MYBETRIQ and MYBETRIQ granules in pediatric NDO patients were conducted under IND 069416.
`
`At the meeting with Astellas held on November 6, 2019, FDA agreed that the development program
`appeared sufficient to support the submission of an efficacy and safety supplement and new NDA for the
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`proposed indication for mirabegron tablets and granules for treatment of NDO in pediatric patients. Based
`on these comments, Astellas canceled pre-NDA meeting.
`3.2 General Pharmacology and Pharmacokinetic Characteristics
`Pharmacology
`
`Mirabegron, an agonist of the human beta-3 adrenergic receptor (AR), relaxes
`the detrusor smooth muscle during the storage phase of the urinary bladder fill-
`void cycle by activation of beta-3 AR which increases bladder capacity.
`Mirabegron
`No clinically significant ECG abnormalities or QTcF prolongation were
`observed in Study 178-CL-206A
`
`Mechanism of Action
`
`Active Moieties
`QT Prolongation
`General Information
`
`Bioanalysis
`
`Healthy vs. Patients
`
`Drug exposure at steady
`state (Mean ± SD)
`
`Range of effective dose
`or exposure
`
`Maximally tolerated
`dose or exposure
`
`Pharmacodynamics
`
`Dose Proportionality
`
`Accumulation
`
`Variability (CV)
`
`Absorption
`Bioavailability
`Fasted Tmax (Median and
`Range)
`Food Effect
`Following a High-Fat
`Meal
`(Fed/fasted) [90% CI]
`
`Two liquid chromatography–mass spectrometry (LC-MS) methods were used to
`measure plasma mirabegron concentrations.
`No comparison of PK between pediatric NDO patients and healthy pediatrics
`was conducted.
`
`AUC0-t for PED25: 166.3 ng*h/mL (children, N = 1, SD not calculated);
` 137.8 ± 53.1 ng*h/mL (adolescents, N = 3)
`AUC0-t for PED50: 310.1 ± 163.1 ng*h/mL (children, N = 43);
` 291.6 ± 171.8 (adolescents, N = 24)
`Dose-response analysis for mean volume voided in adult patients with
`overactive bladder showed that 52%, 85%, and 98% of the maximum efficacy
`was achieved at the doses of 25 mg, 50 mg, and 100 mg QD, respectively. The
`mean steady-state AUC0-t in adult patients receiving Myrbetriq tablets 25 mg
`QD was 69 ng*h/mL.
`300 mg QD for 14 days and a single dose of 400 mg in adult patients
`The mean systolic blood pressure increased by 5.9 mm Hg and the mean
`diastolic blood pressure increased by 2.3 mm Hg above baseline in patients less
`than 8 years of age on MYRBETRIQ/MYRBETRIQ Granules at a dose
`equivalent of MYRBETRIQ 50 mg daily dose in adults.
`PopPK analysis showed that both MYRBETRIQ and MYRBETRIQ Granules
`exhibited more than proportional PK in pediatric patients in the dose range of
`PED25 – PED50.
`Tablets: children (fed) 1.6 - 1.8; adolescents (fed) 1.6 - 2.4 (Study 178-CL-202)
`Tablets: children (fed) AUC 50.8 – 64.6%, Cmax 67.6 – 72.6%;
` adolescents (fed) AUC 28.1 – 52.0%, Cmax 57.4 – 81.6%
`Granules: AUC (fed) 62.3%, Cmax (fed) 63.7%
`
`Tablets: 29% at 25 mg dose and 35% at 50 mg dose
`Tablets: 3.95 h (3.47 – 4.27 h)
`Drug
`component
`Tablets
`Granules
`
`AUC0-∞
` 43% [37% - 49%]
` 55% [50% - 61%]
`
`Tmax (Median, hour)
`Cmax
` 40% [31% - 52%] Fed: 3.0, Fasted: 4.0
`37% [29% - 47%] Fed: 3.0, Fasted: 4.0
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` Tablets: 29.0 ± 6.1 h; Granules: 26.0 ± 5.8 h
` Tablets: children 113 ± 63 L/h; adolescents 230 ± 137 L/h
` Granules: 254 ± 165 L/h
`
`64% of dose recovered in feces and urine is metabolized.
` CYP3A4, CYP2D6, butylcholinesterase, uridine diphospho-
`glucuronosyltransferases (UGT), and possibly alcohol dehydrogenase
`
`Steady-state Vd/F: 4895 – 13726 L
`71%
`In vitro data showed that mirabegron is a substrate of P-gp, OCT1, OCT2 and
`OCT3
`
`Distribution
`Volume of Distribution
`Plasma Protein Binding
`Substrate transporter
`systems
`Elimination
`Terminal Elimination
`half-life (Mean ± SD)
`CL/F (Mean ± SD)
`Metabolism
`Fraction metabolized
`(% dose)
`Primary metabolic
`pathway(s)
`Excretion
`Primary excretion
`-- mirabegron in feces: 34% (approximately 0% unchanged)
`pathways (% dose) ±SD
`-- mirabegron in urine: 55% (approximately 25% unchanged)
`In vitro interaction liability (as a perpetrator)
`Inhibition/Induction of
`Mirabegron is a moderate and time-dependent inhibitor of CYP2D6, and a weak
`metabolism
`inhibitor of CYP3A.
`Inhibition/Induction of
`Mirabegron is a weak inhibitor of P-gp.
`transporter systems
`PED25: pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the mirabegron 25 mg
`tablet once daily.
`PED50: pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the mirabegron 50 mg
`tablet once daily.
`3.3 Clinical Pharmacology Review Questions
`
`3.3.1 To what extent does the available clinical pharmacology information provide pivotal or
`supportive evidence of effectiveness?
`
`Based on cross-study comparison, clinical pharmacology information showed that pediatric subjects’
`exposure to mirabegron fell within the range of adult exposures, and the mean steady-state exposure in
`pediatric patients was higher than that in adult patients. PopPK analysis showed that the steady-state
`AUC0-t values of mirabegron for pediatric subjects in pivotal efficacy study (Study 178-CL-206A)
`receiving PED50 (pediatric dose targeted to achieve steady-state exposures similar to those of adults
`administered the mirabegron 50 mg tablet once daily) fell within the range (42 – 854 ng*h/mL) of
`observed adult exposures receiving 50 mg once daily (NDA 202611, original submission). The median
`steady-state AUC0-t values in children (277 ng*h/mL) and adolescents (260 ng*h/mL) patients receiving
`PED50 were slightly higher than that (188 ng*h/mL) in adults receiving 50 mg once daily. The steady-
`state AUC0-t values of mirabegron for pediatric subjects in Study 178-CL-206A receiving PED25
`(pediatric dose targeted to achieve steady-state exposures similar to those of adults administered the
`mirabegron 25 mg tablet once daily) fell within the range (17 – 578 ng*h/mL) of observed adult
`exposures receiving 25 mg once daily (NDA 202611, original submission). The median steady-state
`AUC0-t values in children (166 ng*h/mL) and adolescents (137 ng*h/mL) patients receiving PED25 were
`higher than that (69 ng*h/mL) in adults receiving 50 mg once daily. Refer to Section 3.3.2 for more
`information.
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`3.3.2 Is the proposed dosing regimen appropriate for the general patient population for which the
`indication is being sought?
`
`Yes, the proposed dose regimen is appropriate for treatment of NDO in pediatric patients aged 3 years and
`older. The proposed pediatric regimen is supported by clinical efficacy and safety data in pediatric
`patients, matching to adult drug exposure, and exposure-response for safety. For more information related
`to clinical efficacy and safety data in pediatric patients, refer to clinical and statistical reviews in
`DARRTS.
`
`Mirabegron exposure matching:
`The approved starting and maximum doses for adult patients with overactive bladder (OAB) is 25 mg QD
`and 50 mg QD, respectively. MYBETRIQ and MYBETRIQ granules are not bioequivalent. PopPK
`simulation predicted that mirabegron granule formulation had 57.1% lower bioavailability compared to
`tablet formulation in pediatric patients. In Study 178-CL-206A, the starting pediatric dose PED25 and the
`maximum pediatric dose PED50 for MYBETRIQ and MYBETRIQ granules were optimized to match
`steady-state mirabegron exposures in adults taking MYBETRIQ 25 mg tablet QD and 50 mg tablet QD,
`respectively. Based on popPK simulation, the body weight categories for oral suspension dosing selection
`were determined to be 11-< 22 kg, 22-<35 kg and >=35 kg. For oral suspension, the PED25 doses of 24,
`32, and 48 mg (3, 4, and 6 mL) and FED50 doses of 48, 64, and 88 mg (6, 8, and 11 mL) were selected
`for the three body weight groups, respectively (Table 3.3.2.1). The body weight cutoff for tablet dosing
`selection was determined as 35 kg. Subjects >= 35 kg could take tablets at doses of 25 mg and 50 mg for
`PED25 and PED50, respectively.
`
`Table 3.3.2-1. Body weight-based PED25 and PED50 doses for MYBETRIQ and MYBETRIQ granules
`in pediatric NDO patients in Study 178-CL-206A
`
`Source: Summary of Clinical Pharmacology Studies, Table 4
`
`According to clinical pharmacology review team’s analysis, in Study 178-CL-206A, the proposed starting
`doses (3 mL for body weight range 11 kg to less than 22 kg; 4 mL for body weight range 22 kg to less
`than 35 kg) generated median steady-state AUC0-t similar to or slightly higher than that in adult patients
`taking MYBETRIQ 25 mg tablet QD (Figure 3.3.2-1). Refer to Section 4.3 Population PK Analysis for
`more information.
`
`Figure 3.3.2-1. A comparison of AUC for starting dose of mirabegron oral suspension in NDO patient
`with body weight less than 35 kg*
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`* The red dash line corresponding to the targeted AUC exposure in adults, which is 69 and 188 ng*h/mL for starting and
`maximum dose, respectively.
`Source: Reviewer’s popPK analysis
`
`The individual steady-state AUC0-t values for pediatric patients in Study 178-CL-206A taking PED50
`dose (68 out of 71 patients that had measurable PK concentrations) were calculated using popPK analysis
`and compared graphically to that of adults taking MYBETRIQ 50 mg tablets by age and body weight
`category (Figure 3.3.2-2). All pediatric subjects’ exposure fell within the range of adult exposures, and
`the majority fall within the 5th-95th percentile of adult data. The median steady-state AUC0-t values across
`age- and body weight-based subgroups were similar to or slightly higher than that in adults (188
`ng*h/mL). Refer to Section 4.3 Population PK Analysis for more information.
`
`Figure 3.3.2-2. Steady-state AUC at PED50 for pediatric patients in Study 178-CL-206A compared to adult
`mirabegron exposure at 50 mg by age (left) and body weight (right) category
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`Reference ID: 4757121
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`*The boxplots represent percentiles for the pediatric subgroups: the box shows the 25th, 50th, and 75th percentiles, and the ends of
`the whiskers are the 5th and 95th percentile in each category. The distribution of adult exposures is shown as annotations on the
`plots: solid black lines represent the minimum and maximum, the solid red line is the median, and the gray shaded band is the 5th-
`95th percentile of adult exposures. The adult exposure distribution was based on individual predicted exposures from the final
`population PK model in adults [Study No. 178-PK-015 in approved mirabegron ER tablet].
`Source: IR response 2020-Dec-14, Figure 1
`
`For the oral suspension, while 88 mg or 11 mL was administered in pediatric patients with body weight ≥
`35 kg in Study 178-CL-206A, the Applicant proposed to reduce the dose of oral suspension to 80 mg or
`10 mL in the drug label in order to dose the oral suspension with a single dosing device administration.
`The Applicant provided popPK simulation results to support the proposed dose reduction. As shown in
`Figure 3.3.2-3, for each body weight in the population, the median and 5th and 95th percentiles for
`predicted AUCs were calculated and plotted versus body weight. Based on the simulation data, the
`proposed dose reduction from 88 mg QD to 80 mg QD had a limited impact on the median steady-state
`AUCs in pediatric patients with body weight ≥ 35 kg. The oral suspension dose of 80 mg QD generated
`mirabegron exposures in pediatric patients comparable to that in adult patients. The proposed dose
`reduction appears reasonable. Refer to Section 4.3 Population PK Analysis for more information.
`
`Figure 3.3.2-3. Simulated impact of dose reduction from 88 mg QD to 80 mg QD on the steady-state
`AUC in pediatric patients with body weight ≥ 35 kg taking oral suspension in Study 178-CL-206A (left
`plot 88 mg QD and right plot 80 mg QD)*
`
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`*The orange line is the target AUC level (188 ng*h/mL) which is determined from adult study data in approved tablet
`formulation. The red curve is the median simulated AUC, and the two blue curves represent the 5th and 95th percentiles of
`predicted AUCs.
`Source: IR response 2021-Jan-11, Figure 1
`
`Exposure-response for safety:
`The Applicant conducted mirabegron exposure-response analysis for vital sign endpoints including pulse
`rate, blood pressure, and QTcF interval. No trend was observed with systolic blood pressure, diastolic
`blood pressure, and QTcF interval at the observed range of AUC0-t (0 – 870 ng*h/mL) or Cmax (0 – 80
`ng/mL) (Figure 3.3.2-4 and Figure 3.3.2-5). A positive trend is noted for pulse rate or heart rate in the
`pediatric studies. PopPK analysis showed that the mean ± SD steady-state AUC0-t of mirabegron in
`children and adolescents taking PED50 in Study 178-CL-206A was 310 ± 163 and 292 ± 172 ng*h/mL,
`respectively. The mean ± SD steady-state Cmax of mirabegron in children and adolescents taking PED50
`was 20.6 ± 13.6 and 18.4 ± 12.5 ng/mL, respectively. At the observed mirabegron exposure levels in
`pediatric patients, no obvious increase in heart rate was observed.
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`Reference ID: 4757121
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`Figure 3.3.2-4. Change from baseline mean pulse rate, QTcF interval, and systolic and diastolic blood
`pressure versus individual predicted mirabegron steady-state AUC0-t for patients in Study 178-CL-206A
`
`*Solid blue line (grey shaded region) represents prediction (95% confidence interval) from a linear regression. Steady-state
`AUC0-t calculated based on the dose administered on the day of observation.
`Source: IR response 2021-Jan-14, Figure 4
`
`Figure 3.3.2-5. Change from baseline mean pulse rate, QTcF interval, and systolic and diastolic blood
`pressure versus individual predicted mirabegron steady-state Cmax for patients in Study 178-CL-206A
`
`*Solid blue line (grey shaded region) represents prediction (95% confidence interval) from a linear regression. Steady-state Cmax
`calculated based on the dose administered on the day of observation.
`Source: IR response 2021-Jan-14, Figure 5
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`Reference ID: 4757121
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`In Study 178-CL-206A, mean systolic blood pressure (SBP) in children aged ≥ 3 years and < 12 years
`increased from baseline by 9.7%, 7.0% and 11.1% at weeks 12, 24, and 52, respectively. The blood
`pressure increases were larger in patients aged 4 – 7 years. Exposure-response analysis for change in SBP
`was conducted in children patients (Figure 3.3.2-6). Although 10-20% increase in SBP from baseline was
`observed in 3 among 5 children with AUC > 500 ng*h/mL, more than 10% increase in SBP was also
`observed in childre