Background: Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program for duloxetine in the pediatric MDD population, which consisted of three clinical studies, provided extensive data on the safety, tolerability, and pharmacokinetics of duloxetine across a wide dose range in pediatric patients of differing ages, sex, body weights, and sexual maturation.
Objectives: The objectives were to characterize the pharmacokinetics of duloxetine based on population modeling following daily oral administration in children and adolescents aged 7-17 years diagnosed with MDD; to estimate the magnitude of between- and within-patient variability; to identify potential patient factors affecting duloxetine pharmacokinetics, and to compare duloxetine pharmacokinetics in the pediatric population with those characterized in adults.
Methods: The analyses meta-dataset was created from pharmacokinetic and demographic data available from one phase II (open-label) and two phase III (randomized, double-blind) clinical trials of duloxetine in children and adolescents. Patients received 20-120 mg of oral duloxetine once daily. Duloxetine concentrations (a total of 1,581 concentrations) were obtained from 428 patients: 34% were children (aged 7-11 years) and 66% were adolescents (aged 12-18 years). Population modeling analyses were performed using nonlinear mixed-effects modeling and the first-order conditional estimation method with interaction. Patient factors were assessed for their potential influence on duloxetine apparent clearance (CL/F) and apparent volume of distribution (V d/F). Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the pediatric population were compared with those in adults.
Results: Duloxetine pharmacokinetics in pediatric patients was described by a one-compartmental model. Typical values of CL/F, V d/F, and half-life (t 1/2) at 60 mg/day of duloxetine were 79.7 L/h, 1,200 L, and 10.4 h, respectively. The between-patient variability in CL/F and V d/F was 68 and 87%, respectively, while within-patient variability was 57% (proportional error) and 2.04 ng/mL (additive error). Body surface area (BSA), dose, and race had a statistically significant effect on duloxetine pharmacokinetics. With a 2.2-fold increase in BSA, the CL/F increased about twofold. A sixfold increase in dose (20 to 120 mg) decreased CL/F by 32%. In American Indian patients, V d/F was 131% higher than the other races combined. Age, sex, body mass index, serum creatinine, cytochrome P450 2D6 predicted phenotype, and menarche status did not have a statistically significant effect. Estimates of CL/F and V d/F were higher in the pediatric population than in adults; subsequently, the average steady-state duloxetine concentration was approximately 30% lower in the pediatric population than in adults.
Conclusions: Duloxetine pharmacokinetics was similar in children and adolescents with MDD. The statistically significant effects of dose, BSA, and race on duloxetine pharmacokinetics in pediatric patients did not appear to be clinically meaningful. At a given dose, the typical steady-state duloxetine concentrations in the pediatric population were lower than in adults, and the distribution of steady-state duloxetine concentrations in pediatric patients were typically in the lower range of concentrations in adults.