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Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model

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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

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.

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Acknowledgments

All procedures conformed to the Guide for the Care and Use of Laboratory Animals, 8th edition, issued by the US National Academy of Sciences. Fluoxetine and norfluoxetine assays were performed at the West Coast Metabolomics Center, an NIH Regional Resource Core, under the supervision of Mine Palazoglu. Erica Unger, Pennsylvania State University, performed the CSF analysis. Andrew Campbell, PhD, MPH, Andrew Campbell Consulting, performed the PK analysis. The authors appreciate the contribution of CNPRC Research Services personnel in conducting the dosing and blood sampling for the single-dose studies and Alicia Bulleri for the additional technical assistance. This study was supported by NIH grants R01HD065826 (Golub) and OD011107 (Lewin).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Environmental Toxicology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA

    Mari S. Golub

  2. California National Primate Research Center, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA

    Casey E. Hogrefe

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  1. Mari S. Golub
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  2. Casey E. Hogrefe
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Correspondence to Mari S. Golub.

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Online Resource 1

Fluoxetine data of individual subjects from the single-dose studies. The MAOA genotype is based on MAOA VNTR polymorphisms of 5, 6, or 7 repeats in the promoter region. 5/5 females, 5/- males, 6/6 females, and 6/- males are classified as hi-MAOA based on high transcription rate. 7/7 females and 7/- males are classified as low-MAOA based on low transcription rates for this polymorphism. 5-HTTLPR genotype is based on short (S) and long (L) forms of the serotonin transporter linked polymorphic region (5HTTLPR), with the S form resulting in lower transcription rates. Males or females are classified by allele as L/L, S/L or S/S (JPEG 259 kb)

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Golub, M.S., Hogrefe, C.E. Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model. Psychopharmacology 231, 4041–4047 (2014). https://doi.org/10.1007/s00213-014-3537-y

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  • DOI: https://doi.org/10.1007/s00213-014-3537-y

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