Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model.
BACKGROUND
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.


OBJECTIVE
The goal of this study was 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 day 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 area under the curve (AUC) and C max values were seen, while T max and absorption/elimination half-lives were minimally influenced by dose. A dosage of 2 mg/kg day 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
A dose of 2 mg/kg day 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's therapeutic and potential adverse effects in children.
Department of Environmental Toxicology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA, msgolub@ucdavis.edu.
Mari S
MS
Golub
Casey E
CE
Hogrefe
D015102:3,4-Dihydroxyphenylacetic Acid / Q000134:cerebrospinal fluid; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005473:Fluoxetine / Q000493:pharmacokinetics*; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D012701:Serotonin / Q000134:cerebrospinal fluid; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*
D015102:3,4-Dihydroxyphenylacetic Acid; D005473:Fluoxetine; D006719:Homovanillic Acid; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors