Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model

Abstract

Rationale-The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only psychopharmacological agent approved for use in children. While short-term studies of side effects have been performed, long-term consequences for brain development are not known. Such studies can be performed in appropriate animal models if doses modeling therapeutic use in children are known.Objectives-To identify a daily dose of fluoxetine in juvenile monkeys which would result in serum fluoxetine and norfluoxetine concentrations in the therapeutic range for children.Methods-Juvenile (2.5 year old rhesus monkeys, n=6) received single administration of doses of 1, 2 and 4 mg/kg-d fluoxetine on a background of chronic dosing at an intermediate level to provide steady state conditions to model therapeutic administration. Using nonlinear modeling, standard pharmacokinetic parameters were derived. Cerebrospinal fluid monoamine neurotransmitters were assayed to confirm the pharmacological effects.Results-Dose-dependent AUC and Cmax values were seen while Tmax and absorption/ elimination half-lives were minimally influenced by dose. A dosage of 2 mg/kg-d given over a 14 week period led to steady state serum concentrations of active agent (fluoxetine + norfluoxetine) similar to those recorded from drug monitoring studies in children. Cisternal cerebrospinal fluid concentrations of serotonin increased significantly over the 14 week period, while concentrations of the serotonin metabolite (5-HIAA) were lower but not significantly different.Conclusions-2 mg/kg/d fluoxetine in juvenile rhesus monkeys provides an internal dose similar to therapeutic use in children and will help establish a valuable animal model for understanding fluoxetine therapeutic and potential adverse effects in children.

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine

“…Vehicle controls received only the flavorful vehicle. A dose of 2.0 mg/kg was known to be therapeutic in adult rhesus (48–52) and determined to be in the therapeutic range for juvenile rhesus (53). During the two years of treatment (from 1 to 3 years of age) the dose was initiated at 1.6 mg/kg for the first 11 months and increased to 2.4 mg/kg for the remainder of the study.…”

Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration

“…Fluoxetine dose selection was based on information in the human and non-human primate literature and on a preliminary pharmacokinetic/pharmacodynamic study to provide steady-state circulating levels of fluoxetine/norfluoxetine in the range reported for therapeutic use of fluoxetine in children (Golub and Hogrefe, 2014). Dosing was initiated at one-year of age at 1.6mg/kg/day and adjusted to 2.4 mg/kg/day after 11 months, one month before the one-year sampling reported here.…”

Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions

“…The fluoxetine variable corresponds to a dose of ∼2.0 mg/kg over the two-year treatment period, a dose based on preliminary pharmacokinetic studies (Golub and Hogrefe, 2014), as well as previous experience with this drug in macaques (Anderson, 2004; Clarke et al, 1999; Clarke et al, 1998; Fontenot et al, 2009; Fontenot et al, 2005; Sawyer and Howell, 2011; Shrestha et al, 2014). For 11 months prior to behavior data collection, a dose of 1.6 mg/kg was administered.…”

“…The ages of the rhesus macaque subjects in the present study (one to four years of age) correspond roughly to four to twelve year-old children. Previous reports from this project have described dose selection (Golub and Hogrefe, 2014), metabolomic biomarkers of drug action (He et al, 2014), bone growth (Golub et al, 2015), sleep disturbance (Golub and Hogrefe, 2016), and social interaction (Golub et al, 2016). …”