ACUTE CARDIOTOXICITY OF THE ANTI-HIV DIDEOXYNUCLEOSIDE, F-DDA, IN THERAT

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected b y the NCI as a clinical trial candidate. A recent report that high, si ngle doses of F-ddA produce cardiotoxicity in rats prompted the presen t investigation whose objective was to quantitate this effect and esta blish a relationship between this toxicity and F-ddA plasma concentrat ions. Microscopic examination of cardiac tissues for degenerative lesi ons established the effects of F-ddA and ddA on three iv schedules [da ily x 1 (2.5-250 mg/kg); daily x 5 (125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg)] using 8- to 12-week-old female Sprague-Dawley rats. For both F-ddA and ddA, the g roup mean severity of the cardiac lesions was dose-dependent and propo rtional to the measured plasma concentrations of the undeaminated pare nt drugs. F-ddI and ddI, the respective deaminated catabolites of F-dd A and ddA, were essentially nontoxic in this study (iv, 250 mg/kg, dai ly x 1 and daily x 5), since plasma concentrations exceeding 2 mM prod uced only minimal cardiac lesions. The cardiomyopathy of F-ddA was min imal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, r esulting in higher plasma concentrations of F-ddA relative to ddA at a ny given time for any given dose. Neither F-ddA nor ddA was more cardi otoxic on a repeated iv schedule (daily x 5) than when administered on ly once, suggesting that rat cardiotoxicity is related to C-max rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with iv F-dd A administration when the F-ddA plasma concentration approaches 300 mu M, 30-50 times the anticipated therapeutic level in humans. (C) 1995 Society of Toxicology