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Pharmacologic Considerations for Oseltamivir Disposition

Focus on the Neonate and Young Infant

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Abstract

Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile.

Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug.

In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current ‘information gaps’ deserving of future study are presented.

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Acknowledgements

We appreciate the thoughtful review provided by Suzanne R. Hill, MD, and Charles Penn, PhD. This research was supported in part by a grant from the WHO. The findings, interpretations, and conclusions expressed in this paper are entirely those of the authors and should not be attributed in any manner whatsoever to the WHO. Gregory Kearns is a member of the Committee on Essential Medicines, WHO. Susan Abdel-Rahman and Jason Newland have no conflicts of interest to declare that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Division of Clinical Pharmacology and Medical Toxicology, The Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Suite 0411, Kansas City, Missouri, 64108, USA

    Susan M. Abdel-Rahman (Professor of Pediatrics) & Gregory L. Kearns

  2. Division of Infectious Diseases, The Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, USA

    Jason G. Newland

  3. Department of Pediatrics, University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri, USA

    Susan M. Abdel-Rahman (Professor of Pediatrics), Jason G. Newland & Gregory L. Kearns

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  1. Susan M. Abdel-Rahman
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Correspondence to Susan M. Abdel-Rahman.

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Abdel-Rahman, S.M., Newland, J.G. & Kearns, G.L. Pharmacologic Considerations for Oseltamivir Disposition. Pediatr-Drugs 13, 19–31 (2011). https://doi.org/10.2165/11536950-000000000-00000

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