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Antimicrobial Agents and Chemotherapy, November 2009, p. 4753-4761, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.01541-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System{triangledown}

Gerhard Hoffmann,1* Christoph Funk,1 Stephen Fowler,1 Michael B. Otteneder,1 Alexander Breidenbach,1 Craig R. Rayner,2 Tom Chu,3 and Eric P. Prinssen4

Non-Clinical Safety,1 Pharma Partnering,2 Discovery Neuroscience, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland,4 Clinical Pharma, Pharmaceuticals Division, Roche Palo Alto LLC, Palo Alto, California3

Received 19 November 2008/ Returned for modification 28 March 2009/ Accepted 20 August 2009

Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.

* Corresponding author. Mailing address: Pharma Research, F. Hoffmann-La Roche Ltd., Bldg. 70/127, CH-4070 Basel, Switzerland. Phone: 41 61 688 83 93. Fax: 41 61 688 29 08. E-mail: gerhard.hoffmann{at}roche.com

{triangledown} Published ahead of print on 31 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4753-4761, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.01541-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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