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respectively (Figure 11.8). Cell-based metabolism studies showed that high levels
of PSI-6206-TP were formed when replicon cells and primary human hepato-
cytes were incubated with [
3
H]-PSI-7851. In primary human hepatocytes incu-
bated with 5 mM[
3
H]-PSI-7851, the level of PSI-6206-TP reached an intracellular
concentration of approximately 100 mM. Studies to determine the intracellular
half-life of PSI-6206-TP revealed that after reaching steady-state levels, the
concentration of PSI-6206-TP decreased with a mean half-life of 38.1
16.1 h.
This exceptionally high level of intracellular triphosphate formation gave
us confidence that if PSI-7851 could make it to the liver we should see
in vivo ecacy in humans. In fact, the levels of triphosphate metabolite
generated by delivering PSI-7851 were much higher than what was observed
with PSI-6130/RG7128. Since RG7128 shows exceptional clinical ecacy,
we expected to see ecacy in humans with PSI-7851 if it could reach the
liver.
11.4.3 PSI-7851 Clinical Characterization and Studies
As noted above, PSI-7851 has a number of favorable preclinical characteristics
which made it an attractive development candidate for the treatment of chronic
HCV infection. We speculated that the long intracellular half-life of PSI-6206-
TP and the demonstrated improvements in in vitro antiviral potency, coupled
with the improved liver/plasma ratio observed in preclinical studies, would
translate into a potent antiviral which would potentially be administered QD at
a lower daily dose than RG7128. As of January 2010, PSI-7851 has been
evaluated following single ascending doses in healthy volunteers and in a three-
day monotherapy study in patients infected with genotype 1 HCV.
11.4.3.1 Single Ascending Dose Study in Healthy Volunteers
Single oral doses of PSI-7851 or matching placebo were administered to 42
healthy subjects enrolled in four alternating cohorts to receive either placebo or
PSI-7851 at doses of 25, 50, 100, 200, 400, and 800mg. A solution formulation
at a dose of 50mg was also compared to the 50mg capsule dose. Safety
assessments were conducted throughout the study and plasma exposure to PSI-
7851 and its metabolites (PSI-352707 and the uridine nucleoside metabolite,
PSI-6206) were evaluated. Single ascending doses of PSI-7851 were generally
safe and well-tolerated in this study, with no dose-limiting toxicities or a
maximum tolerated dose identified. The PK results demonstrated a systemic
exposure profile consistent with rapid uptake of the drug by the liver with low
plasma exposure to PSI-7851 and PSI-352707, and relatively higher plasma
PSI-6206 exposure. The 50mg solution dose resulted in plasma exposures 15-
16% higher than the capsule formulation.
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