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

Rittig, Søren; Baka-Ostrowska, Małgorzata; Tøndel, Camilla; Walle, Johan Vande; Kjaeer, Birgitta; Passier, Paul; Bosman, Brigitte; Stroosma, Otto B.; Tannenbaum, Stacey

doi:10.1016/j.jpurol.2019.10.009

Cited by 11 publications

(7 citation statements)

References 23 publications

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“…A total of 114 patients from three studies 18 were included in the pooled population PK analysis. A two‐compartment model with transit compartment absorption and first‐order elimination was considered to adequately characterize the concentration‐time profile of mirabegron in children and adolescents.…”

Section: Resultsmentioning

confidence: 99%

“…For PK analysis, four samples of venous blood at steady state at the optimal dose (after 10 days at the same dose) were collected over 2 sampling days (Day 1: predose trough sample, Day 2: one predose trough sample and two postdose samples separated by at least 1 h). Since PK sampling was sparse and skewed towards the early phase of the profile, the data from this study were pooled with two phase I studies in patients with NDO or overactive bladder aged 5 to less than 18 years (NCT02211846) and aged 3 to less than 12 years (NCT02526979) 18 . The PK profile of mirabegron was then characterized using a population PK modeling approach for maximum (peak) plasma drug concentration (C max ), time to reach maximum (peak) plasma concentration following drug administration (t max ), area under the plasma concentration‐time curve from time 0 to 24 h (AUC 24 ), trough plasma concentration (C trough ), apparent total clearance of the drug from plasma (CL/F), and apparent volume of distribution (Vz/F).…”

Section: Methodsmentioning

confidence: 99%

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Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open‐label, phase 3, dose‐titration study

Baka-Ostrowska

Bolong²,

Persu

et al. 2021

Neurourology and Urodynamics

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Aims: To evaluate the efficacy and safety of mirabegron in children and adolescents (aged 3 to <18 years) with neurogenic detrusor overactivity (NDO) using clean intermittent catheterization. Methods:In this open-label, multicenter, baseline-controlled, Phase III study (NCT02751931), participants received once-daily mirabegron at an adult dose equivalent of 25 mg. Dose was increased to 50 mg equivalent unless there were safety/tolerability concerns. The primary efficacy endpoint was change from baseline to Week 24 in maximum cystometric capacity (MCC). Secondary urodynamic assessments, Pediatric Incontinence Questionnaire (PIN-Q), Patient Global Impression of Severity (PGI-S), Clinician Global Impression of Change (CGI-C), and Acceptability questionnaires were included. Results: Overall, 86 participants (55 aged 3 to <12 years, 31 aged 12 to <18 years) received treatment; 68 were included in efficacy assessments. A statistically significant increase in MCC from baseline to Week 24 was observed (87.20 ml, 95% confidence interval: 66.07, 108.33; p < .001); this increase was apparent from Week 4. Significant increases in bladder compliance, bladder volume until first detrusor contraction, average volume per catheterization, maximum daytime catheterized volume and number of dry days per week.Significant decreases in detrusor pressure and number of leakage episodes per day were also observed. Significant improvement in PGI-S but not PIN-Q was observed. Most participants reported their condition had either much or very much improved using the CGI-C. Mirabegron was well tolerated in this population with a profile aligned with that in adults. Conclusions: Mirabegron was effective and well-tolerated in the treatment of pediatric patients with NDO.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open‐label, phase 3, dose‐titration study

Baka-Ostrowska

Bolong²,

Persu

et al. 2021

Neurourology and Urodynamics

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“…Mirabegron has been used as an alternative treatment option in pediatric patients with neurogenic bladder due to spina bifida [6]. While the safety and pharmacokinetics of mirabegron have been studied in neurogenic and non-neurogenic detrusor overactivity [18], this is the first study to report the use of this agent in children with valve bladder.…”

Section: Discussionmentioning

confidence: 99%

Safety and short-term efficacy of mirabegron in children with valve bladder: a pilot study

2021

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Aims This pilot study aims to assess the short-term efficacy and safety of mirabegron in valve bladder, an important cause of persistent hydronephrosis after successful treatment of posterior urethral valves (PUV). Methods Twenty-two patients with early valve bladder (no residual PUV; persistent hydronephrosis, wetting and urodynamic evidence of detrusor overactivity) were included. Three subjective parameters: frequency, wetting episodes; patient perception of bladder condition score (PPBC) and four objective parameters: uroflow index (UI = Qave/Qmax), voided volume (VV = voided volume/ expected bladder capacity), maximum filling pressure (P det-max) and society of fetal urology (SFU) hydronephrosis grading were analysed pre-and post-3-month treatment with mirabegron (0.5-1 mg/kg/day). All patients were observed for heart rate, BP, ECG changes during therapy. Results There was significant reduction (p = 0.001) in mean frequency (pre 15; post 10), wetting episodes (pre 5; post 2) and PPBC (pre 4; post 3). There was significant improvement (p = 0.01) in mean UI (pre 0.3; post 0.5), VV (pre 0.54; post 0.72), Pdet-max (pre 42; post 25) and hydronephrosis grade (pre 3.5; post 2.2). There were no significant side effects. Conclusion This pilot study establishes short-term efficacy and safety of mirabegron in valve bladder with overactivity. Further larger long-term studies are warranted.

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“…In this perspective, the pharmaceutical armamentarium for β3-AR agonism is relatively equipped and β3-AR agonists are also being tested in repurposing trials for cardiovascular and metabolic conditions. 8,178,179 In addition, recently mirabegron, a selective β3-AR agonist, has been demonstrated safe and well-tolerated in children 180,181 and even approved for the pediatric population. 182 In this sense, we can at least begin to dream of the next trip.…”

Section: Discussionmentioning

confidence: 99%

β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

Filippi

Pini

Cammalleri

et al. 2021

Medicinal Research Reviews

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The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert

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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

Cited by 11 publications

References 23 publications

Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open‐label, phase 3, dose‐titration study

Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: An open‐label, phase 3, dose‐titration study

Safety and short-term efficacy of mirabegron in children with valve bladder: a pilot study

β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

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