Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

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 (0À24) 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 (po0.0001), 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.

Sex differences in pharmacokinetics of antidepressants

“…No sex differences were found in a sample of children and adolescents [64] and in a sample of Japanese patients [65]. However, in 170 depressed patients, men had a larger volume of distribution [66] and in 75 outpatients, male patients showed a better dose--concentration correlation than female patients [67].…”

The Effect of CYP2D6 Polymorphisms on the Response to Pain Treatment for Pediatric Sickle Cell Pain Crisis

“…We chose to analyze codeine metabolism because: 1) codeine is the most commonly prescribed oral opioid for outpatient sickle cell pain at our institution, and 2) the important clinical effects of CYP2D6 polymorphisms have been shown with codeine activation, as well as the activation or metabolism of many commonly used drugs, including tramadol, and many cardiovascular or psychoactive drugs. 9,[20][21][22] There are study limitations that need to be addressed. First, we did not measure enzyme activity; however, the calculated activity scores closely approximate phenotype, and account for duplications, providing an accurate assessment of the enzyme activity.…”

Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders

“…Clinicians should be aware of the potential activating side effects of SSRIs (insomnia, agitation, tremor, and anxiety), especially in young children [1299-1301]. Regulatory bodies in many countries have issued black-box warnings about suicidal ideation/suicide attempts with the use of antidepressants in patients younger than 19 years.…”

“…More conservative dosing strategies may be needed especially in younger children or those with low body weight [1301]. …”