A NONCLINICAL SAFETY ASSESSMENT OF DIDANOSINE, A NUCLEOSIDE ANALOG WITH ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS ACTIVITY

Didanosine (2',3'-dideoxyinosine) is one of a group of dideoxynucleosi de analogues with anti-human immunodeficiency virus activity including 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytosine (ddC), 2',3'-dide hydro-2',3'-dideoxythymidine (d4T), and 3'-azido-3'-deoxythymidine (AZ T). This assessment of the safety of didanosine is a series of in vivo and in vitro toxicology studies that were performed to support the us e of didanosine in the treatment of human retroviral diseases. Toxicol ogy studies with orally administered didanosine included single-dose a nd 1-, 3-, and 12-month multiple-dose studies, reproductive assessment s, mutagenicity assays, and carcinogenicity studies. The assessment of plasma concentrations and urinary excretion demonstrated that all spe cies were exposed to didanosine when administered orally. The most con sistent clinical toxicities included alimentary tract disturbances, an d clinicopathologic changes included mild leukopenia, borderline anemi a, thrombocytopenia, and elevated uric acid, alanine, and aspartate am inotransferase levels. Microscopic lesions included lymphoid depletion , bone marrow hypocellularity, skeletal muscle alterations (especially in the esophagus), and cytologic alterations in the kidney tubules. P rimary microscopic changes in the liver consisted of vascular lesions and evidence of reduced blood flow, which included pigmented Kupffer c ells and hepatocellular changes with centrolobular necrosis, hemosider osis, and acidophilic bodies. Adrenal degeneration was also noted. The extensive genotoxicity data demonstrated that although there were wea kly positive findings with didanosine in the in vitro assays, presumab ly because of nucleotide pool imbalance, didanosine lacks intrinsic ge notoxic potential in vivo. This was corroborated by 2-year carcinogeni city studies that showed no clear evidence of carcinogenicity in rats or mice. There were no effects on reproductive performance or fetal de velopment. In conclusion, the toxicity of didanosine has been extensiv ely evaluated in a comprehensive series of nonclinical, laboratory ani mal studies.