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Isis Pharmaceuticals (J.M.L., S.H., L.A.T., A.L., D.K.) and
TSI
Mason Laboratories (A.Z.)
The disposition of ISIS 2922, a phosphorothioate oligonucleotide
for treatment of cytomegalovirus associated retinitis, was evaluated in
rabbits. Vitreous humor and retina samples were collected from rabbits
that received a single intravitreal injection of 66 µg
[14C]-labeled ISIS 2922 and were analyzed
using anion exchange HPLC. Four hr postdosing, the concentration of
ISIS 2922 in vitreous humor was 3.3 µM. The elimination of ISIS 2922 from the vitreous humor exhibited first-order kinetics with a
t1/2 of 62 hr. By 10 days postdosing, the
mean concentration of ISIS 2922 in rabbit vitreous humor had decreased
to 0.17 µM, which represented 22% of the total radioactivity
remaining in the vitreous. The remaining 78% coeluted on anion
exchange HPLC with shorter oligonucleotides. In retina, ISIS 2922 accumulated over the first 5 days postdosing, reaching a maximum
concentration of 3.5 µM, and then declined thereafter with an
estimated t1/2 of 79 hr. By 10 days
postdosing when only 24% of the total radioactivity in the retina was
parent compound, the concentration of ISIS 2922 remained at 1.6 µM,
which was 10 times higher than the concentration in the vitreous humor. Whereas the elimination of full-length ISIS 2922 and total
radioactivity from the vitreous humor occurred at nearly equal rates,
ISIS 2922 disappeared more rapidly than did total radioactivity from
the retina, suggesting a greater role for metabolism in the clearance process from retina than the vitreous. Alternatively, the results are
consistent with metabolites being cleared from the vitreous at
approximately the same rate as parent compound while in the retina
metabolites may be cleared more slowly. The data were analyzed with a
user-defined pharmacokinetic model, which was then used to predict the
potential for accumulation of ISIS 2922 during clinical dosing.
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