PHARMACOKINETICS OF A POTENTIAL HUMAN CYTOMEGALOVIRUS THERAPEUTIC, A PHOSPHOROTHIOATE OLIGONUCLEOTIDE, AFTER INTRAVITREAL INJECTION IN THE RABBIT

The disposition of ISIS 2922, a phosphorothioate oligonucleotide for t reatment of cytomegalovirus associated retinitis, was evaluated in rab bits. Vitreous humor and retina samples were collected from rabbits th at received a single intravitreal injection of 66 mu g [C-14]-labeled ISIS 2922 and were analyzed using anion exchange HPLC, Four hr postdos ing, the concentration of ISIS 2922 in vitreous humor was 3.3 mu M. Th e elimination of ISIS 2922 from the vitreous humor exhibited first-ord er kinetics with a t(1/2) of 62 hr, By 10 days postdosing, the mean co ncentration of ISIS 2922 in rabbit vitreous humor had decreased to 0.1 7 mu M, which represented 22% of the total radioactivity remaining in the vitreous, The remaining 78% coeluted on anion exchange HPLC with s horter oligonucleotides, In retina, ISIS 2922 accumulated over the fir st 5 days postdosing, reaching a maximum concentration of 3.5 mu M, an d then declined thereafter with an estimated t(1/2) of 79 hr. By 10 da ys postdosing when only 24% of the total radioactivity in the retina w as parent compound, the concentration of ISIS 2922 remained at 1.6 mu M, which was 10 times higher than the concentration in the vitreous hu mor, Whereas the elimination of full-length ISIS 2922 and total radioa ctivity from the vitreous humor occurred at nearly equal rates, ISIS 2 922 disappeared more rapidly than did total radioactivity from the ret ina, suggesting a greater role for metabolism in the clearance process from retina than the vitreous, Alternatively, the results are consist ent with metabolites being cleared from the vitreous at approximately the same rate as parent compound while in the retina metabolites may b e cleared more slowly, The data were analyzed with a user-defined phar macokinetic model, which was then used to predict the potential for ac cumulation of ISIS 2922 during clinical dosing.