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The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation

(2020) JOURNAL OF PEDIATRIC UROLOGY. 16(1). p.31.e1-31.e10
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Abstract
Introduction Mirabegron, a selective beta 3-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.
Keywords
Pediatrics, Perinatology, and Child Health, Urology, enuresis, bladderdysfunction, Mirabegron, Neurogenic detrusor overactivity, Overactive bladder, Pediatrics, Pharmacokinetics, BETA(3)-ADRENOCEPTOR AGONIST, URINARY-INCONTINENCE, PLACEBO, STANDARDIZATION, SOLIFENACIN

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MLA
Rittig, Sören, et al. “The Pharmacokinetics, Safety, and Tolerability of Mirabegron in Children and Adolescents with Neurogenic Detrusor Overactivity or Idiopathic Overactive Bladder and Development of a Population Pharmacokinetic Model–Based Pediatric Dose Estimation.” JOURNAL OF PEDIATRIC UROLOGY, vol. 16, no. 1, 2020, pp. 31.e1-31.e10, doi:10.1016/j.jpurol.2019.10.009.
APA
Rittig, S., Baka-Ostrowska, M., Tøndel, C., Vande Walle, J., Kjaeer, B., Passier, P., … Tannenbaum, S. (2020). The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation. JOURNAL OF PEDIATRIC UROLOGY, 16(1), 31.e1-31.e10. https://doi.org/10.1016/j.jpurol.2019.10.009
Chicago author-date
Rittig, Sören, Małgorzata Baka-Ostrowska, Camilla Tøndel, Johan Vande Walle, Birgitta Kjaeer, Paul Passier, Brigitte Bosman, Otto Stroosma, and Stacey Tannenbaum. 2020. “The Pharmacokinetics, Safety, and Tolerability of Mirabegron in Children and Adolescents with Neurogenic Detrusor Overactivity or Idiopathic Overactive Bladder and Development of a Population Pharmacokinetic Model–Based Pediatric Dose Estimation.” JOURNAL OF PEDIATRIC UROLOGY 16 (1): 31.e1-31.e10. https://doi.org/10.1016/j.jpurol.2019.10.009.
Chicago author-date (all authors)
Rittig, Sören, Małgorzata Baka-Ostrowska, Camilla Tøndel, Johan Vande Walle, Birgitta Kjaeer, Paul Passier, Brigitte Bosman, Otto Stroosma, and Stacey Tannenbaum. 2020. “The Pharmacokinetics, Safety, and Tolerability of Mirabegron in Children and Adolescents with Neurogenic Detrusor Overactivity or Idiopathic Overactive Bladder and Development of a Population Pharmacokinetic Model–Based Pediatric Dose Estimation.” JOURNAL OF PEDIATRIC UROLOGY 16 (1): 31.e1-31.e10. doi:10.1016/j.jpurol.2019.10.009.
Vancouver
1.
Rittig S, Baka-Ostrowska M, Tøndel C, Vande Walle J, Kjaeer B, Passier P, et al. The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation. JOURNAL OF PEDIATRIC UROLOGY. 2020;16(1):31.e1-31.e10.
IEEE
[1]
S. Rittig et al., “The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation,” JOURNAL OF PEDIATRIC UROLOGY, vol. 16, no. 1, pp. 31.e1-31.e10, 2020.
@article{8658312,
  abstract     = {{Introduction

Mirabegron, a selective beta 3-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.}},
  author       = {{Rittig, Sören and Baka-Ostrowska, Małgorzata and Tøndel, Camilla and Vande Walle, Johan and Kjaeer, Birgitta and Passier, Paul and Bosman, Brigitte and Stroosma, Otto and Tannenbaum, Stacey}},
  issn         = {{1477-5131}},
  journal      = {{JOURNAL OF PEDIATRIC UROLOGY}},
  keywords     = {{Pediatrics,Perinatology,and Child Health,Urology,enuresis,bladderdysfunction,Mirabegron,Neurogenic detrusor overactivity,Overactive bladder,Pediatrics,Pharmacokinetics,BETA(3)-ADRENOCEPTOR AGONIST,URINARY-INCONTINENCE,PLACEBO,STANDARDIZATION,SOLIFENACIN}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{31.e1--31.e10}},
  title        = {{The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model–based pediatric dose estimation}},
  url          = {{http://dx.doi.org/10.1016/j.jpurol.2019.10.009}},
  volume       = {{16}},
  year         = {{2020}},
}

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