Subscribe Now Subscribe Today
Science Alert Home Journals at Science Alert For Authors For Subscribers Contact Us
   
International Journal of Virology
  Year: 2009 | Volume: 5 | Issue: 3 | Page No.: 119-130
DOI: 10.3923/ijv.2009.119.130
Oseltamivir is Devoid of Specific Behavioral and Other Central Nervous System Effects in Juvenile Rats at Supratherapeutic Oral Doses
C. Freichel, E. Prinssen, G. Hoffmann, L. Gand, M. Beck, T. Weiser and A. Breidenbach

Abstract:
In order to support the potential use of the antiviral oseltamivir in children aged <1 year, a non-clinical study was undertaken to identify any potential behavioral and other effects of supratherapeutic doses of oseltamivir in juvenile rats in relation to plasma and brain drug exposure levels. Separate toxicology and toxicokinetic cohorts of 7-day old rats were divided into paired treatment groups such that individual dose groups from both cohorts received either vehicle or single oral doses of oseltamivir at 300, 500, 600, 700, 850 and 1000 mg kg-1. All rats were observed twice daily for mortality and moribundity. Approximately 2 h after dosing, modified Functional Observational Battery (FOB) data were recorded for all dose groups in the toxicology cohort and clinical observations were performed in the toxicokinetic cohort for changes in posture, convulsions and tremors. Blood and brain samples were taken from the second cohort for toxicokinetic analysis. Post-necropsy assessments included microscopic examination of brain tissue. Young adult rats (aged approximately 6 weeks) were also included in the study (1000 mg kg-1 single oral dose only) for comparison of oseltamivir toxicokinetics. No effects on FOB parameters were recorded at 300 mg kg-1. At 500 and 600 mg kg-1, changes noted in the FOB were inconclusive because of inconsistent responses in the control group. Following doses of ≥600 mg kg-1, drug-related changes indicative of non-specific systemic toxicity were noted. Therefore, the in-life assessments did not identify any specific CNS behavior that would predict toxicity in these very young animals. Necropsy revealed no histological changes at any dose level evaluated. Compared to levels following therapeutic doses, very high oseltamivir and oseltamivir carboxylate plasma concentrations of up to approximately 42,000 and 9000 ng mL-1, respectively, were already observed at the lowest dose of 300 mg kg-1 in juvenile rats. For all dose levels, the ratios of the oseltamivir and oseltamivir carboxylate concentrations in brain to those in plasma were low (≤0.3). The no observed effect level for single-dose oseltamivir was 300 mg kg-1, which, because of the very high oseltamivir and oseltamivir carboxylate plasma levels, suggests a wide safety margin in children younger than 1 year old.
 [Fulltext PDF]   [Fulltext HTML]   [XML: Abstract + References]   [References]   [View Citation]  [Report Citation]
How to cite this article:

C. Freichel, E. Prinssen, G. Hoffmann, L. Gand, M. Beck, T. Weiser and A. Breidenbach, 2009. Oseltamivir is Devoid of Specific Behavioral and Other Central Nervous System Effects in Juvenile Rats at Supratherapeutic Oral Doses. International Journal of Virology, 5: 119-130.

DOI: 10.3923/ijv.2009.119.130

URL: http://scialert.net/abstract/?doi=ijv.2009.119.130

 
COMMENT ON THIS PAPER
.
 
 
 
 

 

 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

                 home       |       journals        |       for authors       |       for subscribers       |       asci
          © Science Alert. All Rights Reserved