Use of tolterodine in children with neurogenic detrusor overactivity: relationship between dose and urodynamic response.
OBJECTIVE
Three exploratory studies were conducted to investigate the pharmacokinetics (PK) and safety of tolterodine in children 1 month to 15 years old with neurogenic detrusor overactivity. We urodynamically evaluated the dose and concentration effects of tolterodine to establish safe and effective dosing regimens.


METHODS
Three open-label, dose escalating studies were conducted in children with stable neurological disease and detrusor overactivity. In studies 1 (patient aged 1 month to 4 years) and 2 (5 to 10 years) patients received 0.03, 0.06 and 0.12 mg/kg tolterodine solution day twice daily for 4 weeks each. In study 3 (patient age 11 to 15 years) patients received 2, 4 and 6 mg tolterodine extended-release capsules once daily for 4 weeks each. PK was assessed after 8 weeks, urodynamic assessments were conducted after each 4-week dosing period and 3-day micturition diaries were completed.


RESULTS
Patients in studies 1 (19) and 2 (15) showed some dose related increases in volume to first detrusor contraction and cystometric bladder capacity. In study 3 (11 patients) there were no obvious dose-response relationships. PK results from studies 1 and 2 suggest that there was no apparent effect of age (< or =10 y) on these parameters. In study 3 time of maximum observed serum concentration and apparent terminal half-life were delayed, which is consistent with the extended-release formulation. Tolterodine was well tolerated, and there was no apparent relationship between tolterodine dose and adverse events in any study.


CONCLUSIONS
These results support the safety of age and body weight adjusted dosing regimens for further clinical evaluation of tolterodine in children with neurogenic detrusor overactivity.
Ellsworth
Pamela I
PI
Division of Urology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts 01655, USA. ellsworp@ummhc.org
Borgstein
Niels G
NG
Nijman
Rien J M
RJ
Reddy
Pramod P
PP
D000293:Adolescent; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003408:Cresols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012449:Safety; D000068737:Tolterodine Tartrate; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000187:drug effects; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy*; D014563:Urodynamics / Q000187:drug effects
D001559:Benzhydryl Compounds; D003408:Cresols; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate