PHARMACOKINETICS OF CIDOFOVIR IN MONKEYS - EVIDENCE FOR A PROLONGED ELIMINATION PHASE REPRESENTING PHOSPHORYLATED DRUG

After intravenous administration of [C-14]cidofovir to African green m onkeys (43 mg/kg, 29.5 mu Ci/kg), the drug distributed rapidly into ex tracellular fluid. Concentrations of radioactivity in plasma were desc ribed by a three-compartment model with alpha, beta, gamma half-lives of 0.67, 3.02, and 36.0 hr, respectively (N = 3). These phases are bel ieved to represent renal elimination, efflux of free cidofovir from ce lls, and efflux from cells of cidofovir produced from dephosphorylatio n of metabolites, respectively. Less than 5% of the dose was phosphory lated, based on the proportion of total AUC in the gamma-phase. The cl earance of cidofovir (211 +/- 16.6 ml/hr/kg) was dependent on dose and exceeded the theoretical glomerular filtration rate. Concentrations o f cidofovir in kidney declined with a half-life of 23 hr and were >1,0 00-fold higher than plasma levels by 120 hr. Clearance of cidofovir af ter multiple intravenous doses of 4.9 mg/kg/day (18.5 mu Ci/kg/day) de creased significantly by day 10, consistent with the observed nephroto xicity. Oral and subcutaneous bioavailabilities of cidofovir were 21.8 +/- 9.44 and 98.5 +/- 15.8%, respectively. After intravenous administ ration of [C-14]cidofovir to cynomolgus monkeys (10 mg/kg, 100 mu Ci/k g) alone or 1 hr after oral probenecid (30 mg/kg), mean +/- SD (N = 3) urinary recoveries of total radioactive dose were 91.4 +/- 11.3% and 94.4 +/- 29.8%, respectively, at 7 days postdose. The mean +/- SD half -lives of the terminal elimination phases were 33.3 +/- 10.6 and 24.4 +/- 5.0 hr, respectively. Cidofovir accounted for 98% of the radioacti vity recovered in urine; the remainder was attributed to cidofovir pho sphocholine. The prolonged elimination phase observed in monkeys is co nsistent with the long intracellular half-life of phosphorylated cidof ovir in vitro and supports infrequent dosing of the drug for antiviral therapy.