Comparison of anti-influenza virus activity and pharmacokinetics of oseltamivir free base and oseltamivir phosphate

Jin Soo Shin; Keun Bon Ku; Yejin Jang; Yi-Seul Yoon; Daeho Shin; Oh Seung Kwon; Yun Young Go; Seong Soon Kim; Myoung Ae Bae; Meehyein Kim

doi:10.1007/s12275-017-7371-x

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Comparison of anti-influenza virus activity and pharmacokinetics of oseltamivir free base and oseltamivir phosphate: Jin Soo Shin ¹, Keun Bon Ku ¹, Yejin Jang ¹, Yi-Seul Yoon ¹, Daeho Shin ^1,2, Oh Seung Kwon ^1,2, Yun Young Go ^1,2, Seong Soon Kim ^2,3, Myoung Ae Bae ^2,3, Meehyein Kim ^1,2; Journal of Microbiology 2017;55(12):979-983.
DOI: https://doi.org/10.1007/s12275-017-7371-x
Published online: December 7, 2017

¹Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea, ²Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea, ³Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon 34113, Republic of Korea¹Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea, ²Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea, ³Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon 34113, Republic of Korea

Corresponding author: Meehyein Kim , Tel: +82-42-860-7540,

Received: 29 August 2017 • Revised: 29 October 2017 • Accepted: 30 October 2017

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Abstract

Influenza viruses are major human respiratory pathogens that cause high morbidity and mortality worldwide. Currently, prophylactic vaccines and therapeutic antiviral agents are used to prevent and control influenza virus infection. Oseltamivir free base (OSV-FB), a modified generic antiviral drug of Tamiflu (oseltamivir phosphate, OSV-P), was launched in the Republic of Korea last year. Here, we examine the bioequivalence of these two compounds by assessing their antiviral efficacy in infected cells and in a mouse model. It was observed that both antivirals showed comparable efficacy against 11 different influenza A and B viruses in vitro. Moreover, in mice infected with influenza A virus (mouse-adapted A/Puerto Rico/8/34), they showed a dose-dependent therapeutic activity and alleviated infection-mediated reductions in body weight, leading to significantly better survival. There was histopathological disappearance of virus-induced inflammatory cell infiltration of the lung after oral treatment with either antiviral agent (at 10 mg/kg). Pharmacokinetic analysis also exhibited similar plasma concentrations of the active drug, oseltamivir carboxylate, metabolised from both OSVB and OSV-P. This is the first report showing bioequivalence of OSV-FB to its phosphate salt form in the mouse system. The free base drug has some beneficial points including simple drug formulation process and reduced risk of undesirable cation-phosphate precipitation within solution. The long term stability of OSV-FB requires further monitoring when it is provided as a national stock in readiness for an influenza pandemic.

Keywords: oseltamivir free base;influenza virus;antiviral;histopathology;pharmacokinetics

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Comparison of anti-influenza virus activity and pharmacokinetics of oseltamivir free base and oseltamivir phosphate

J. Microbiol. 2017;55(12):979-983. Published online December 7, 2017

DOI: https://doi.org/10.1007/s12275-017-7371-x

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