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Kempf, D.J. et al.

Dale J. Kempf, Cheri Klein, Hui-Ju Chen, Larry L. Klein, Clinton Yeung, John T. Randolph, Yau Y. Lau, Linda E. Chovan, Zhiwen Guan, Lisa Hernandez, Teresa M. Turner, Peter J. Dandliker, Kennan C. Marsh,

Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir.

Inhibitors of hepatitis C virus (HCV) protease have shown marked antiviral activity in short-term clinical studies in HCV-infected individuals. The interaction of the investigational HCV protease inhibitors VX-950 and SCH 503034 with ritonavir, a potent inhibitor of cytochrome P450 3A, was studied in vitro and in vivo. In rat and human liver microsomes, the metabolism of VX-950 and SCH 503034 was strongly inhibited by the presence of 4 microM ritonavir. Upon co-dosing either VX-950 or SCH 503034 with ritonavir in rats, plasma exposure of the HCV protease inhibitors was increased by > 15-fold, and plasma concentrations 8 h after dosing were increased by > 50-fold. A human pharmacokinetic model of VX-950 co-administered with low-dose ritonavir suggested that improved efficacy and/or dosing convenience may be feasible by pharmacokinetic enhancement with ritonavir.[1]

References

Pharmacokinetic enhancement of the hepatitis C virus protease inhibitors VX-950 and SCH 503034 by co-dosing with ritonavir. Kempf, D.J., Klein, C., Chen, H.J., Klein, L.L., Yeung, C., Randolph, J.T., Lau, Y.Y., Chovan, L.E., Guan, Z., Hernandez, L., Turner, T.M., Dandliker, P.J., Marsh, K.C. Antivir. Chem. Chemother. (2007) [Pubmed]

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