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

Abstract Didanosine (2′,3′-dideoxyinosine) is one of a group of dideoxynucleoside analogues with anti—human immunodefidiency virus activity including 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxycytosine (ddC), 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), and 3′-azido-3′-deoxythymidine (AZT). This assessment of the safety of didanosine is a series of in vivo and in vitro toxicology studies that were performed to support the use of didanosine in the treatment of human retroviral diseases. Toxicology studies with orally administered didanosine included single-dose and 1-, 3-, and 12-month multiple-dose studies, reproductive assessments, mutagenicity assays, and carcinogenicity studies. The assessment of plasma concentrations and urinary excretion demonstrated that all species were exposed to didanosine when administered orally. The most consistent clinical toxicities included alimentary tract disturbances, and clinicopathologic changes included mild leukopenia, borderline anemia, thrombocytopenia, and elevated uric acid, alanine, and aspartate aminotransferase levels. Microscopic lesions included lymphoid depletion, bone marrow hypocellularity, skeletal muscle alterations (especially in the esophagus), and cytologic alterations in the kidney tubules. Primary microscopic changes in the liver consisted of vascular lesions and evidence of reduced blood flow, which included pigmented Kupffer cells and hepatocellular changes with centrolobular necrosis, hemosiderosis, and acidophilic bodies. Adrenal degeneration was also noted. The extensive genotoxicity data demonstrated that although there were weakly positive findings with didanosine in the in vitro assays, presumably because of nucleotide pool imbalance, didanosine lacks intrinsic genotoxic potential in vivo. This was corroborated by 2-year carcinogenicity studies that showed no clear evidence of carcinogenicity in rats or mice. There were no effects on reproductive performance or fetal development. In conclusion, the toxicity of didanosine has been extensively evaluated in a comprehensive series of nonclinical, laboratory animal studies.