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

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.

Long-term efficacy and safety of solifenacin in pediatric patients aged 6 months to 18 years with neurogenic detrusor overactivity: results from two phase 3 prospective open-label studies.

INTRODUCTION: The standard recommended treatment for neurogenic detrusor overactivity (NDO) is clean intermittent catheterization combined with an antimuscarinic agent. However, the adverse systemic side-effects of oxybutynin, the most widely used agent, are of concern. OBJECTIVE: To evaluate the efficacy and safety of solifenacin in pediatric patients with NDO, aged 6 months-<5 years and 5-<18 years. STUDY DESIGN: Two open-label, baseline-controlled, phase 3 studies were conducted in pediatric patients with NDO. Patients were treated with sequential doses of solifenacin oral suspension (pediatric equivalent doses 2.5-10 mg) for 12 weeks to determine each patient's optimal dose, followed by a fixed dose ≥40-week treatment period. Primary efficacy endpoint was change from baseline in maximum cystometric capacity (MCC) after 24 weeks. Secondary endpoints included bladder compliance, bladder volume until first detrusor contraction (>15 cmH2O), number of overactive detrusor contractions (>15 cmH2O), maximum catheterized volume (MCV)/24 h, and incontinence episodes/24 h. Safety parameters were treatment-emergent adverse events (TEAEs), serious adverse events, laboratory variables, vital signs, electrocardiograms, and ocular accommodation and cognitive function assessments. RESULTS: After 24 weeks, MCC had significantly increased compared with baseline in patients aged 6 months -<5 years and 5-<18 years (37.0 ml and 57.2 ml, respectively; P < 0.001; Fig.). Improvement was also observed after 52 weeks' treatment. Significant changes were observed from baseline to week 24 in all secondary endpoints in both age groups: increase in bladder compliance, increase in bladder volume to first detrusor contraction as a percentage of expected bladder capacity, reduction in the number of overactive detrusor contractions, increase in MCV, and decreased incontinence episodes. TEAEs were mostly mild or moderate, and there were no new drug-related TEAEs compared with adult studies. Age-related improvements were noted in ocular accommodation and cognitive function. DISCUSSION: These long-term multicenter investigations demonstrated the efficacy and safety of solifenacin in pediatric patients with NDO. The observed increases in MCC were clinically relevant and demonstrated that an increase in fluid volume can be accommodated in the bladder prior to reaching intravesical pressures that endanger kidney function and/or are associated with leakage or discomfort. Solifenacin was well tolerated with low incidences of constipation and dry mouth (typically associated with antimuscarinics), central nervous system-related side-effects, and facial flushing. CONCLUSION: Solifenacin was effective and well tolerated in pediatric patients with NDO, aged 6 months-<18 years, suggesting that it is a viable alternative to oxybutynin, the current standard of care. STUDIES ARE REGISTERED AT CLINICALTRIALS.GOV: NCT01981954 and NCT01565694.

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.

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.

The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients.

INTRODUCTION: In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. MATERIAL AND METHODS: A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. RESULTS: Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). CONCLUSIONS: Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

Complications after primary bladder exstrophy closure - role of pelvic osteotomy.

INTRODUCTION: Bladder exstrophy is the most common form of the exstrophy - epispadias complex. It is observed in 1:30 000 life births, about four times more often in boys than in girls. Iliac osteotomy is used to facilitate bringing together pubic bones and to minimize the tension of fused elements. To analyze complications after primary bladder exstrophy closure with a special consideration of the role of pelvic osteotomy. MATERIAL AND METHOD: It is a retrospective study evaluating 100 patients (chosen by chance out of 356) with bladder exstrophy (65 boys and 35 girls), treated in Pediatric Urology Department of the Children's Memorial Health Institute in Warsaw, Poland between 1982 and 2006. All children underwent primary bladder exstrophy closure, among them 32 elsewhere. Primary bladder exstrophy closure with contemporary iliac osteotomy was done in 36 children. In the rest 64 patients bladder was closed without osteotomy, regardless child's age. RESULTS: Dehiscence after primary closure followed with bladder prolaps occurred in 31 patients, among them 13 out of 68 (19%) operated in our department and 18 out of 32 (56%) operated in another hospital. Primary bladder exstrophy closure with contemporary iliac osteotomy was done in 32 infants above 72 hours of life. CONCLUSIONS: Osteotomy performed at primary bladder exstrophy closure diminishes the risk of wound dehiscence independently of patient's age. Posterior iliac osteotomy is sufficient and safe and could be repeated if necessary.

[Urinary tract infections in children by pediatric urologist]. / Zakazenia ukladu moczowego u dzieci okiem urologa dzieciecego.

Urinary tract infection (UTI) is the most common infection disease in all age. From the pediatric urology point of view, difficulty in bladder emptying is the most favorable factor for UTI. Early ultrasonographic (USG) investigation is necessary to detect urinary obstruction and urolithiasis. It is important to perform USG with filled bladder and directly after micturition. Voiding cystourethrogram (VCUG) should be done after UTI in small children (below 3 years of age). For the detection of renal damage the DMSA-scan is the most sensitive method that should be performed during UTI and 6 months later. In case of bladder dysfunction suspicion the uroflowmetry is substantial. Detection of leucocyturia give rise to microbiological diagnosis and proper treatment. UTI with fever needs antibiotic therapy started in first 24 hours to prevent renal damage. Risk factor for recurrences are bladder dysfunction and residual urine. Prophylaxis should not be restricted to the use of antibiotics or other prophylactic agents but must include the efficient management of bladder and bowel dysfunction and proper liquids administration.

Bladder augmentation and continent urinary diversion in boys with posterior urethral valves.

Posterior urethral valve (PUV) is a condition that leads to characteristic changes in the bladder and upper urinary tract. Dysfunction of the bladder such as a hyperreflective, hypertonic, and small capacity bladder as well as sphincter incompetence and/or myogenic failure should be adequately treated. Poor compliance/small bladder could be treated with anticholinergics, but bladder augmentation will probably be indicated. Although bladder reconstruction with gastrointestinal segments can be associated with multiple complications, including metabolic disorders, calculus formation, mucus production, enteric fistulas, and malignancy formation, enterocystoplasty is still the gold standard. In contrast to a neuropathic or exstrophic bladder, augmentation of the valve bladder allows spontaneous voiding without significant residual urine in the majority of cases, but some require CIC (clean intermittent cathterization). Augmentation cystoplasty is also an efficient approach in those children who will require kidney transplantation in the future.

[Urinary tract infections--pediatric urologist point of view]. / Zakazenia ukladu moczowego--spojrzenie urologa dzieciecego.

Urinary tract infections (UTI) could present with different clinical forms dependent on intensity and localization of infection and child's age. The symptoms could be non specific in children. Condition that provoke to urinary stasis, especially voiding dysfunction is the favourable factor for UTI appearance. Gram-negative enteric bacteria is the most common pathogen. Urine culture is the basic investigation that allow to identify pathogen and its drug sensitiveness but simultaneous urinalysis is necessary to recognize the inflammation of urinary organs. In addition, the number of leukocytes gives an idea about inflammation intensity. Ultrasonographic (USG) scan is necessary to examine urostasis. DMSA study performed during febrile UTI allow to identify children with acute pyelonephritis and when repeated 6 months later - those with renal scars. A normal USG and DMSA scan during infection makes voiding cystourethrography (VCU) unnecessary in the primary examination. The presence of vesicoureteric reflux (VUR) not always predispose children to renal lesions. Early and appropriate treatment of UTI, especially during the first 24 hours, diminishes the likelihood of renal involvement during the acute phase of infection but does not prevent scar formation. The proper hygiene of the urethral meatus, voiding and drinking habits and preventing of constipation are crucial in UTI prophylaxis.

[Vesicoureteral reflux and urinary tract infections]. / Odplyw pecherzowo-moczowodowy a zakazenia ukladu moczowego.

Understanding the role of urodynamic conditions in the bladder with vesicoureteral reflux (VUR) have changed the cause-effect relationship between vesicoureteral reflux and urinary tract infections (UTI) in children. It is not a presence of UTI itself that decides on VUR appearance but accompanying voiding dysfunction. Dysfunctional voiding causes functional urinary tract obstruction which increases intravesical pressure during storage and voiding, and contributes post-voiding residuals. When intravesical pressure exceed ureteric opening pressure the VUR occurs and UTI develops because of urinary stasis. It was noticed that high voiding pressure contributed 90% of VUR in infants. If bladder dysfunction is a fundamental factor in VUR creation, the treatment of VUR should focus on elimination of this dysfunction. Endoscopic subureteric injection could be used as an additional treatment, particularly reducing recurrences of febrile UT.