1. ¹Departments of Psychiatry and Pediatrics, Case Western Reserve University, University Hospitals of Cleveland, OH, USA
2. ²GlaxoSmithKline,Verona, Italy
3. ³PAREXEL, Baltimore, MD, USA
4. ⁴i3 Research, Basking Ridge, NJ, USA
5. ⁵GlaxoSmithKline, King of Prussia, PA, USA
6. ⁶Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospital and Clinics, Kansas City, MO, USA

Correspondence: Dr RL Findling, Department of Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106-5080, USA. Tel: +1 216 844 1707; Fax: +1 216 844 5883; E-mail: robert.findling@uhhs.com

Received 1 June 2005; Revised 2 September 2005; Accepted 23 September 2005; Published online 23 November 2005.

Abstract

The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive–compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C_max and AUC_(0-24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (p<0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.