BACKGROUND AND OBJECTIVES: Pharmacokinetic studies in children are particularly required for drugs with intensive hepatic and regioselective intestinal elimination and pharmacological effects that may be critical for absorption at therapeutic doses, such as a delay in intestinal transit. One example is the antimuscarinic drug propiverine, the pharmacokinetics of which were evaluated in the present study in children with symptoms of overactive bladder. METHODS: The pharmacokinetics of immediate-release propiverine were studied in a dose-escalating, parallel-group study (propiverine 5, 10 and 15 mg twice daily for 14 days) in 25 subjects (11 females and 14 males aged 5-10 years; bodyweight 17-44 kg; body mass index 14-21 kg/m2) with symptoms of overactive bladder during waking hours. Serum concentration-time curves of propiverine and its major metabolite propiverine N-oxide (M-5) were evaluated up to 3 hours and 8 hours after the first and last administration, respectively, using liquid chromatography with tandem mass spectrometry. The voiding frequency, number of incontinence and urgency episodes, single voided volume and urine flow variables were measured before and after treatment. RESULTS: Significant dose-related increases in the serum exposure (the area under the concentration-time curve, the maximum concentration and the minimum concentration) with propiverine and M-5 in the dose groups < or =0.3 mg/kg and 0.3 to < or =0.45 mg/kg after both single-dose and repeated-dose administration were found. The elimination half-lives of propiverine and M-5 at steady state were no different (mean +/- SD 12.2 +/- 11.2 and 14.5 +/- 9.94 hours, respectively). Higher doses did not result in additional dose-proportional increases in the respective pharmacokinetic parameters, particularly not after repeated-dose treatment. The voiding frequency, voided volume and urge symptoms were beneficially changed from baseline; significant dose-dependent changes were not observed. Most of the adverse events that were probably or possibly drug related were reported for patients in the high-dose group (>0.45 mg/kg). CONCLUSIONS: The disposition of propiverine is dose related after repeated administration of the recommended doses below 0.45 mg/kg (0.3-0.45 mg/kg) twice daily in children aged 5-10 years with symptoms of overactive bladder and urinary incontinence. ( TRIAL REGISTRATION NUMBERS: [clinicaltrials.gov] NCT00795925; [EudraCT] 2004-001243-30).
BACKGROUND AND OBJECTIVES: Pharmacokinetic studies in children are particularly required for drugs with intensive hepatic and regioselective intestinal elimination and pharmacological effects that may be critical for absorption at therapeutic doses, such as a delay in intestinal transit. One example is the antimuscarinic drug propiverine, the pharmacokinetics of which were evaluated in the present study in children with symptoms of overactive bladder. METHODS: The pharmacokinetics of immediate-release propiverine were studied in a dose-escalating, parallel-group study (propiverine 5, 10 and 15 mg twice daily for 14 days) in 25 subjects (11 females and 14 males aged 5-10 years; bodyweight 17-44 kg; body mass index 14-21 kg/m2) with symptoms of overactive bladder during waking hours. Serum concentration-time curves of propiverine and its major metabolite propiverine N-oxide (M-5) were evaluated up to 3 hours and 8 hours after the first and last administration, respectively, using liquid chromatography with tandem mass spectrometry. The voiding frequency, number of incontinence and urgency episodes, single voided volume and urine flow variables were measured before and after treatment. RESULTS: Significant dose-related increases in the serum exposure (the area under the concentration-time curve, the maximum concentration and the minimum concentration) with propiverine and M-5 in the dose groups < or =0.3 mg/kg and 0.3 to < or =0.45 mg/kg after both single-dose and repeated-dose administration were found. The elimination half-lives of propiverine and M-5 at steady state were no different (mean +/- SD 12.2 +/- 11.2 and 14.5 +/- 9.94 hours, respectively). Higher doses did not result in additional dose-proportional increases in the respective pharmacokinetic parameters, particularly not after repeated-dose treatment. The voiding frequency, voided volume and urge symptoms were beneficially changed from baseline; significant dose-dependent changes were not observed. Most of the adverse events that were probably or possibly drug related were reported for patients in the high-dose group (>0.45 mg/kg). CONCLUSIONS: The disposition of propiverine is dose related after repeated administration of the recommended doses below 0.45 mg/kg (0.3-0.45 mg/kg) twice daily in children aged 5-10 years with symptoms of overactive bladder and urinary incontinence. ( TRIAL REGISTRATION NUMBERS: [clinicaltrials.gov] NCT00795925; [EudraCT] 2004-001243-30).