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observed. In fact, no maximum tolerated dose was achieved. However, in
assessing the human PK, it was determined that PSI-6130 was significantly
metabolized to the inactive uridine metabolite, PSI-6206, confirming what was
observed in biochemical studies.
17-19
Further complicating the PK profile, PSI-
6130 was determined to have an approximate oral bioavailability of 25% in
humans. The presence of a significant inactive metabolite in conjunction with
the low bioavailability raised questions about the development path for this
compound. To address the bioavailability and metabolite issues, a prodrug
strategy was proposed. It was hypothesized that a prodrug approach would
deliver enhanced exposure of the parent nucleoside and might protect against
metabolism to the uridine congener.
To obtain an acceptable prodrug of PSI-6130, the prodrug would have to
maintain stability in the gastrointestinal tract, be eciently absorbed, and release
the parent nucleoside once it reached the systemic circulation. A number of
prodrug analogs were assessed where prodrug moieties were attached to the 3
0
-
and/or 5
0
-hydroxyl groups or the N4 amino group of the cytidine base. The
prodrug derivatives included esters, carbonates, carbamates at the 3
0
-and5
0
-
hydroxyl groups and amides, carbamates, and ureas at the cytidine N4 amino
group. The prodrugs were first triaged based on activity in the HCV subgenomic
replicon assay, stability characteristics in simulated gastric and intestinal fluids,
Caco cell permeability profile, and liver S9 stability. The prodrugs that
demonstrated acceptable characteristics in these in vitro studieswereevaluatedin
vivo. Rat and monkey studies were performed to assess plasma levels of parent
nucleoside subsequent to oral administration of the prodrug. Of all the prodrug
derivatives investigated, the 3
0
-and/or5
0
-esters and carbonates provided the best
profile and, ultimately, the 3
0
,5
0
-diisobutryrate ester prodrug RG7128 (20)was
selected for clinical evaluation for the treatment of HCV (Table 11.2).
25
11.3.2 RG7128 Clinical Studies
RG7128 was initially studied in a single protocol which included three distinct
components: a single ascending dose escalation conducted in healthy volun-
teers, a 14-day multiple ascending dose monotherapy evaluation in HCV-
infected patients who had previously failed standard therapy, and a 28-day
combination with pegylated IFN (Pegasys
s
) and RBV (Copegus
s
) in both
treatment-naı¨ ve patients infected with HCV genotype 1 and treatment-experi-
enced patients with HCV genotypes 2 or 3. This approach allowed for very
rapid early clinical development by realizing the synergies inherent in a single
protocol. To date, RG7128 has been generally well tolerated and is in Phase 2b
development as of January 2010.
11.3.2.1 Single Ascending Dose Study in Healthy Volunteers
Single oral doses of RG7128 from 500mg up to 9000mg were administered to
46 healthy subjects in an escalating fashion, with PK and safety assessments
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