|
CNS Toxicity Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/ kg/ day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/ day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/ kg/ day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/ kg/ day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/ kg/ day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/ kg/ day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/ day. Text Continues Below
Similar CNS vascular lesions have been observed with several other drugs of this class. There were cataracts in female rats after two years of treatment with 50 and 100 mg/ kg/ day (22 and 25 times the human AUC at 80 mg/ day, respectively) and in dogs after three months at 90 mg/ kg/ day (19 times) and at two years at 50 mg/ kg/ day (5 times).
Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
