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conducted throughout the study periods. The effect of food was also assessed in
this trial in order to provide guidance with regard to food for the latter portions
of this study. Few adverse events were reported, with headache being the most
frequent, as is commonly observed in healthy volunteer studies. In general, the
compound was well tolerated across the dose range with no safety issues
identified and no maximum tolerated dose noted. Plasma exposure to RG7128
was negligible, as would be expected with the prodrug. Systemic exposure to
PSI-6130 and PSI-6206, the uridine metabolite of PSI-6130, increased with
increasing doses of RG7128, with PSI-6206 accounting for 14-19% of the total
drug exposure over this dose range. Terminal half-life was approximately 5 h
for PSI-6130 and 19 h for PSI-6206. Food increased exposure of PSI-6130 by
approximately 20%. Overall, the PK profile indicated good exposure to the
active moiety, PSI-6130, and no dose-related adverse events or laboratory
abnormalities were observed. Based upon these results, the 14-day multiple-
dose study of RG7128 was initiated in HCV-infected genotype 1 subjects who
previously had failed IFN therapy.
26
11.3.2.2 Multiple Ascending Dose Studies in HCV Genotype 1
Infected Subjects
A 14-day monotherapy study was conducted in 40 HCV genotype 1-infected
patients who had previously failed an IFN-based therapeutic regimen. Single
daily (QD) doses of 750mg or 1500mg, and twice daily (BID) doses of 750mg
or 1500mg, were tested. All regimens resulted in significant reductions in HCV
RNA in a dose-dependent manner. Table 11.3 shows the mean log
10
decline in
plasma HCV RNA in all RG7128 treatment groups. The decline occurred in a
dose-dependent manner and reached nadir values at day 15, suggesting the
potential for further viral suppression with continued therapy, and a low
potential for escape mutations during early dosing. The decrease in HCV RNA
from baseline in the highest cohort, 1500mg BID, ranged from -1.2 to -4.2
log
10
IUmL
1
. One subject's HCV RNA was suppressed below the limit of
detection, 15 IUmL
1
. An important conclusion to be drawn from this inves-
tigation was the apparent benefit of BID dosing over QD dosing due to higher
Table 11.3 Mean plasma HCV RNA (log
10
copies mL
1
) change from base-
line (MAD)
1500mg
QD
Placebo
750mg QD
750mg BID 1500mg BID
Number of
subjects
8
8
8
9
7
Mean log
10
change on
day 15
-0.19
-0.90
-1.48
-2.12
-2.67
Range
0.1 to -0.4
-0.3 to -1.4
-0.8 to -2.3
-1.7 to -3.5
-1.2 to -4.2
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