Pharmacokinetics of orally administered duloxetine in children and adolescents
with major depressive disorder.
Author(s): Lobo ED(1), Quinlan T, Prakash A.
Affiliation(s): Author information:
(1)Lilly Research Laboratories, Eli Lilly and Company, DC 0724, Indianapolis, IN,
46285-0724, USA, lobo_evelyn@lilly.com.
Publication date & source: 2014, Clin Pharmacokinet. , 53(8):731-40
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.
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