Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity

Abstract The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo‐controlled, 12‐week trial in children (5–<12 years) and adolescents (12–<18 years) with OAB. MONKEY and MARMOSET were open‐label, 52‐week trials in children and adolescents or younger children (6 months–<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight‐adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day–1. Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first‐order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz/F), and terminal half‐life (t1/2) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax) was similar. Dose‐normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.


| INTRODUC TI ON
Overactive bladder (OAB) syndrome is defined in children and adolescents, as in adults, on the basis of symptoms of urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia, if there is no proven infection or other obvious pathology. 1,2 Epidemiological studies have indicated that OAB is a highly prevalent syndrome and between 3.2% and 16.6% of pediatric patients can be affected by OAB symptoms. [3][4][5] Pediatric patients predominately experience the stressful symptoms of increased daytime frequency and urgency urinary incontinence. 6 Neurogenic detrusor overactivity (NDO) in pediatric patients, as in adults, is defined as detrusor overactivity, characterized by involuntary detrusor contractions during the filling phase, which has a relevant neurological cause. 1,7 Patients can experience high intravesical pressures and/or vesicoureteral reflux, which can lead to irreversible renal damage, especially when accompanied by urinary tract infections and episodes of acute pyelonephritis. 8 Some antimuscarinics have been recommended as first-line pharmaceutical agents for treating adult patients with OAB symptoms or NDO. 9,10 However, only a few antimuscarinic medications are available for treating pediatric patients with either of these conditions. 11,12 For example, oxybutynin is approved within the EU for treating children who are > 5 years old, whereas trospium is only indicated in patients aged 12 years or older. 13,14 Several clinical investigations have demonstrated the efficacy and safety of the antimuscarinic, solifenacin, for treating adult patients with OAB and NDO. [15][16][17][18][19] These positive findings have led to the approval of solifenacin for treating OAB symptoms in several regions worldwide, including Europe, the United States, and Japan (2.5, 5, and 10 mg tablets and 1 mg ml -1 oral suspension). [20][21][22][23] Further studies have also been conducted with a solifenacin suspension that has been formulated for use in pediatric patients. Solifenacin treatment led to statistically significant improvements in mean voiding frequency and mean volume voided (MVV) following administration to 34 children with newly diagnosed OAB and 138 children with therapy-resistant OAB, respectively. 24,25 In addition, the results of phase III trials in children and adolescents with OAB showed that oral solifenacin suspension was superior to placebo in terms of MVV and was well tolerated over 52 weeks of treatment, with the majority of adverse events being mild or moderate in severity and no treatment-related serious adverse events being reported. 26,27 No unexpected safety concerns were apparent when solifenacin suspension was administered to children and adolescents with NDO and the drug appeared to be an efficacious and well-tolerated treatment, with a minority of patients reporting adverse events, when it was used to treat children with oxybutynin-or tolterodine-refractory NDO. 28,29 Furthermore, two phase III open-label trials in 99 pediatric patients with NDO showed that the use of solifenacin significantly increased maximum cystometric capacity and the antimuscarinic was well tolerated, with most adverse events being mild or moderate in severity. 30 The results of these trials contributed to the European and US approval of oral solifenacin suspension for the treatment of pediatric patients (2-<18 years) with NDO. 31,32 Ascertaining the pharmacokinetics (PK) of potential drugs provides vital information that can be used to determine the optimal dosing regimen to be included in the drug label that informs prescribers. PK studies in healthy adults have shown that solifenacin is suitable for once-daily administration, 33 demonstrates high oral bioavailability, 34 and exhibits PK properties that are not affected by food ingestion. 35 In addition, solifenacin is mainly metabolized by hepatic cytochrome P450 3A4 (CYP3A4), predominately eliminated in the urine (approximately 70%, mostly as metabolites), and displays a high degree of plasma protein binding (approximately 98%, primarily to α 1 -acid glycoprotein [AGP]). 36 Anatomical, physiological, and biochemical differences between children and adults can have a profound effect on the PK and pharmacodynamics of a medication. 37 Therefore, for any medication that will be used in pediatric patients, it is necessary to establish the PK of the drug in this specific population. Two single-dose trials evaluated the PK of solifenacin in pediatric patients with OAB or NDO; 28,38 these trials indicated that similar solifenacin exposures are observed in both patient populations following the administration of a single weight-adjusted dose of the drug. 28 Three subsequent phase III clinical trials, which included PK assessments, have investigated the administration of multiple doses of oral solifenacin succinate suspension to pediatric patients with OAB or NDO. The efficacy and safety results from these trials are briefly mentioned above and have been previously reported. 26,30 The objective of the present investigation was to utilize the data from these trials to characterize the PK of solifenacin through the use of nonlinear mixed effects modeling.

| Ethics
Prior to any trial-related screening procedures being performed, written informed consent was obtained from the parents and/or legal guardians of the patients in all three trials. Assent was obtained from the patients themselves where appropriate. The ethical, scientific, and medical appropriateness of the trials were reviewed by Independent Ethics Committees before they commenced. All three trials were performed in compliance with Good Clinical Practice.

| Trial designs
The designs for all three trials are presented in Figure 1 and inclusion and exclusion criteria are presented in Table S1 This was a double-blind, randomized, placebo-controlled, sequential dose-titration trial conducted in children (5-<12 years) and adolescents (12-<18 years) with OAB (Study 905-CL-076). The methodology has been presented elsewhere. 26 Briefly, patients started urotherapy 39 4 weeks prior to randomization following completion of the screening procedures. After 2 weeks, a single-blind 2-week placebo run-in period was started in combination with the ongoing urotherapy.
After this run-in period, eligible patients, who had not gained sufficient benefit from urotherapy alone, were randomized to receive 12 weeks  Figure 1B and Cadapted from Franco, et al. 30a Every 3 weeks, dose modification of trial drug could be performed to obtain doses of PED2.5, PED5, PED7.5, or PED10. b Weight-adjusted starting dose was equivalent to 5 mg in adults. c The fixed-dose assessment period started when the optimal dose for the patient was reached and it ended at week 52. d Weight-adjusted starting dose was equivalent to 2.5 or 5 mg in adults depending on patient age  dose titration occurred prior to week 12). The PK samples were taken within 3 hours prior to dosing and 1-3, 4-6, and 7-10 hours post dose (four samples in total). One additional blood sample was taken at week 12, 24, or 36 to analyze the AGP level.

| The MARMOSET trial (ClinicalTrials.gov: NCT01981954)
This was an open-label, baseline-controlled, sequential dose-titration trial in younger children (6 months-<5 years) with NDO (Study 905-CL-074). The methodology has been presented elsewhere. 30 Briefly,  and safety (whether the patient experienced bothersome adverse reactions) of the dose. The fixed-dose assessment period started when the optimal dose for the patient was reached and it ended at week 52. PK sampling was performed at one visit or was spread across up to three visits (weeks 12, 24, and/or 36). The PK samples were taken within 3 hours prior to dosing and 1-3, 4-5, and 7-10 hours post dose (four samples in total). One additional blood sample was taken at week 24 to analyze the AGP level.

| Bioanalytical methods
For the PK assessments, samples of venous blood (2 mL, except  For all trials, the precision of the assay was < 2.1%, accuracy was < 9.5%, and the assay range was 20-600 mg dL -1 .

| PK and statistical analyses
Population PK modeling was performed using nonlinear mixed effects modeling software (NONMEM, version 7.3) and solifenacin PK parameters were summarized using descriptive statistics.
To support model stability for the LION trial, the PK data from this trial were pooled with the results from a single-as-

| RE SULTS
Patient demographics and baseline characteristics from all three trials are summarized in Table 1. In total, 194 children and adolescents received treatment with solifenacin in the three trials.

| Doses of solifenacin
All of the patients in the three trials initially received a starting dose of PED5, except for the four patients aged 6 months-<2 years in the MARMOSET trial who received PED2.5 (Table 2). At the time PK sampling occurred, the majority of participants (119/164 patients, 72.6% of those remaining) had been up-titrated in all three trials and were receiving PED10 once daily.

| PK results
The dose-normalized concentration-time profiles for all three trials are shown in Figure 2.

| The LION trial
The final model that was developed for the LION trial was a twocompartment model with first-order oral absorption and a lag time (Table 3A)

| The MONKEY trial
For the MONKEY trial, the final model was a one-compartment model with first-order oral absorption and a lag time (Table 3B). IIV on CL/F, apparent volume of distribution (V/F), and k a as well as additive and proportional residual error were incorporated into the model. FFM was added to the clearance and volume terms as the size parameter for allometric scaling with estimated exponents, and AGP was added to CL/F and V/F with a power model with an estimated exponent. The parameters were precisely estimated and had relatively small standard errors.

TA B L E 3 (Continued)
In the MONKEY trial, higher mean CL/F and V z /F values were obtained for adolescents compared with children (Table 4B), and consistent median t max values were observed across both age groups.
Furthermore, mean t 1/2 was also higher for adolescents (38 hours) in comparison with children (24 hours). The dose-normalized mean AUC and C max results were similar in both children and adolescents ( Figure 3B).

| The MARMOSET trial
The final model for the MARMOSET trial was a one-compartment model with first-order oral absorption and a lag time (Table 3C) C max /D (ng mL -1 mg -1 ) 5.744 (   Abbreviations: AUC/D, dose-normalized area under the plasma concentration-time curve; CL/F, apparent oral plasma clearance; C max /D, dosenormalized maximum plasma concentration; C trough /D, dose-normalized trough plasma concentration; CV, coefficient of variation; NDO, neurogenic detrusor overactivity; OAB, overactive bladder; PK, pharmacokinetic; t 1/2 , terminal half-life; t max , time to maximum plasma concentration; V z /F, apparent volume of distribution during the terminal phase. a Geometric mean = exp(mean(log(x))), geometric CV% = sqrt(exp(sd(log(x))^2)-1)*100. exponents, and AGP was added to CL/F and V/F with a power model with an estimated exponent. As some of the patients were < 2 years old, an ontogeny function for the CYP3A4-mediated portion of the clearance was also included. 40 The parameters were precisely estimated with relatively small standard errors.
Similar mean CL/F and V z /F values were obtained using the final model for both the children aged 6 months-<2 years and those aged 2-<5 years (Table 4C). Furthermore, consistency across the median t max and mean t 1/2 values was also observed for both age groups. The dose-normalized mean AUC and C max results were similar for both the younger and older children ( Figure 3C).

| D ISCUSS I ON
It is imperative to conduct PK analyses and modeling in pediatric patients in order to describe the PK in the pediatric population, to understand the sources of variability in PK, and to inform dosing bone, vital organs, and extracellular fluid and can be used to explain variability in drug clearance. 42,43 Other size metrics such as weight and lean body mass had been investigated in previous solifenacin population PK models, with FFM found to be the most robust factor. In addition, as FFM was used as a metric in clinical decisions, such as the construction of the pediatric dosing tables used in clinical studies, this covariate was selected a priori for addition to the base model. Including AGP on the clearance and volume terms is also reasonable from a physiological perspective.
For drugs like solifenacin with low intrinsic clearance and high plasma protein binding to AGP, 34,44 clearance is approximately proportional to the fraction unbound. As a plasma protein, AGP would also have an impact on the distribution of solifenacin out of the plasma. An ontogeny function for the CYP3A4-mediated portion of solifenacin clearance was also included in the model for the MARMOSET trial; this step was taken as some of the patients in this investigation were < 2 years old and therefore full maturation of their CYP3A4 activity may not have occurred. 40 This investigation showed that the PK characteristics of solifenacin were similar in pediatric patients with OAB and NDO. This finding is particularly reassuring given the differences in physiological characteristics between the two populations, for example the decreased muscle mass that is apparent in children with neurogenic bladder. 45 Overall analysis showed that apparent clearance was similar across the trials (after adjusting for FFM and AGP and including the assumption that CYP3A4 was fully mature). Analysis of the PK parameters across age groups indicated that mean CL/F and V z /F were higher in adolescents than in children, due to ado- for solifenacin that were used in these pediatric trials and the models that were developed to characterize the PK results.
The PK findings from a single-dose trial in pediatric patients (5-<18 years) with NDO have been presented previously (ELEFANT; Study 905-CL-079). 28 Although slightly higher mean CL/F, t 1/2 , V z /F, and median t max results were observed in this single-dose trial, the PK results obtained were broadly similar to the findings from the MONKEY trial. Furthermore, slightly lower mean AUC and C max results were typically obtained in the LION trial compared with the single-ascending dose PK trial in pediatric patients with OAB (GIRAFFE), although similar overall findings were observed. 38 In addition, the results of ELEFANT and GIRAFFE indicated that similar PK data were observed following the administration of single doses of solifenacin to patients with OAB or NDO.
In conclusion, the PK of solifenacin in pediatric OAB or NDO populations were characterized through population PK modeling.
Although higher mean CL/F, V z /F, and t 1/2 were observed for adolescents than for children, similar median t max results were observed for both age groups. Dose-normalized exposure results were similar for both the younger and older patients with either condition. Overall, this investigation showed that pediatric patients with OAB or NDO demonstrate similar PK characteristics for solifenacin.

DATA S H A R I N G S TATE M E NT S
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D I SCLOS U R E S
All the authors are current or former employees of either Astellas