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Antiviral Activity, Pharmacokinetics, Safety, and Tolerability of PSI-7851, a Novel Nucleotide Polymerase Inhibitor for HCV, Following Single and 3 Day Multiple Ascending Oral Doses in Healthy Volunteers and Patients with Chronic HCV Infection
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Reported by Jules Levin
AASLD Nov 2 2009 Boston, MA
Maribel Rodriguez-Torres1, Eric Lawitz2, Stephen Flach3, Jill M. Denning4, Efsevia Albanis4, William Symonds4, and M. Michelle Berrey4
1. Fundacion de Investigacion de Diego, Santurce, PR, USA, 2. Alamo Medical Research, Ltd, San Antonio, TX, USA, 3. Covance Clinical Research Unit, Inc., Madison, WI, USA, 4. Pharmasset, Inc., Princeton, NJ, USA.
BACKGROUND
The nucleotide polymerase inhibitor class has been shown to have
significant potential for the treatment of chronic hepatitis C infection due to
clinical potency, safety and a high barrier to resistance. PSI-7851, a second
generation nucleotide analog, is a phosphoramidate prodrug of β-D-2'-
deoxy-2'-fluoro-2'-C-methyluridine 5'-monophosphate (PSI-6206
monophosphate). In vitro, PSI-6206 does not demonstrate antiviral activity
in the replicon assay because it can not be phosphorylated to the
monophosphate form. However metabolism studies in primary human
hepatocytes demonstrated that the monophosphate of PSI-6206 can be
phosphorylated to the corresponding triphosphate. The triphosphate form
of PSI-6206 (PSI-7409) is a potent inhibitor of the HCV NS5B RNAdependent
RNA polymerase. Therefore, PSI-7851 was developed to
overcome this non-productive phosphorylation step1. PSI-7851 has
enhanced antiviral potency over first generation nucleoside analogs,
achieves high liver to plasma ratios of key metabolites in preclinical studies
and has the potential to be dosed once daily.
1. Furman, et al. 15th Intl Symp on HCV, Oct 2008, San Antonio, TX
2. Gane, et al. J Hepatol 50(Suppl. 1),S380 (2009) (abstract)
3. Reddy, et al. LB#9, AALSD, 2007
4. Lalezari, et al. LB#16, EASL, 2008
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