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Antimicrobial Agents and Chemotherapy, October 2008, p. 3687-3693, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00327-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers ^,

S. S. Jhee,¹ M. Yen,¹ L. Ereshefsky,¹ M. Leibowitz,¹ M. Schulte,² B. Kaeser,² L. Boak,² A. Patel,² G. Hoffmann,² E. P. Prinssen,² and C. R. Rayner^2*

California Clinical Trials, Glendale, California,¹ F. Hoffmann-La Roche Ltd., Basel, Switzerland²

Received 10 March 2008/ Returned for modification 26 May 2008/ Accepted 18 July 2008

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C_max], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C_max, 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C_max CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

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* Corresponding author. Mailing address: F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Bldg. 015/1.006, CH-4070 Basel, Switzerland. Phone: 41(0) 61 688 3133. Fax: 41(0) 61 688 6007. E-mail: craig.rayner{at}roche.com

Published ahead of print on 1 August 2008.

Roche clinical trial number BP21288.

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Antimicrobial Agents and Chemotherapy, October 2008, p. 3687-3693, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00327-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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