The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean ؎ standard deviation terminal half-life of 2.6 ؎ 1.2 h (n ‫؍‬ 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean ؎ standard deviation total clearance of the drug from serum (148 ؎ 25 ml/h/kg; n ‫؍‬ 25) approximated renal clearance (129 ؎ 42 ml/h/kg; n ‫؍‬ 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 ؎ 21 ml/h/kg; n ‫؍‬ 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) is an acyclic nucleotide analog with potent activity against a broad spectrum of herpesviruses, including cytomegalovirus (CMV). The in vivo and in vitro antiviral activities of cidofovir have been reviewed (1). Unlike ganciclovir and other nucleoside analogs currently used for clinical therapy of human herpesvirus infections, cidofovir does not depend on phosphorylation by viral nucleoside kinases to exert its antiviral effect (2). Instead, the drug is phosphorylated to its active form by cellular enzymes. In vitro studies have suggested that the resulting active metabolites are cleared slowly from the intracellular space (2).Preclinical pharmacokinetic studies with radiolabelled cidofovir in rats and mice (10) and in rabbits and monkeys (3) have demonstrated that the majority of the drug is distributed to the kidneys and is excreted in the urine within 24 h of intravenous administration. In monkeys, a fraction of the radioactive dose (approximately 10%) was excreted in a slow elimination phase, with a terminal elimination half-life of 24 to 35 h. This slower excretion phase may reflect the long intracellular half-life of the phosphorylated metabolites of cidofovir (2). In both monkeys and rabbits, approximately 98% of the excreted radioactive dose was present in the urine as unchanged drug. The oral bioavailability of the drug was estimated to be 3% i...

Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, is a novel antiviral nucleotide analogue with potent in vitro and in vivo activity against cytomegalovirus (CMV) and other herpesviruses. Thirty-one human immunodeficiency virus-seropositive patients with asymptomatic CMV excretion were evaluated in a phase I/II study with 2 regimens of cidofovir: cidofovir alone at doses of 0.5, 1.0, 3.0, or 10.0 mg/kg/week (20 patients) and cidofovir at 3.0, 5.0, or 7.5 mg/kg with concomitant oral probenecid, saline prehydration, extended dosing intervals, and drug interruption for proteinuria (19 patients). Prolonged and dose-dependent anti-CMV effect was observed with all cidofovir regimens > or = 3.0 mg/kg. The dose-limiting toxicity of cidofovir was dose- and schedule-dependent nephrotoxicity. Four of 20 patients had serum creatinine levels > or = 2.0 mg/dL after a mean cumulative exposure of 14.8 mg/kg cidofovir alone; however, none of 19 patients receiving the modified regimen had elevated creatinine (mean cidofovir exposure, 32.2 mg/kg). The clinical efficacy of cidofovir and its potential for cumulative nephrotoxicity needs further study in patients with end-organ CMV disease.

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Cidofovir {HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine} is a nucleotide analog with activity against human cytomegalovirus (CMV).A phase I/II dose escalation trial was conducted with asymptomatic human immunodeficiency virus (HIV)-infected patients with CMV viruria to determine its pharmacokinetics, maximally tolerated dose, and preliminary antiviral activity against CMV. Qualitative CMV blood and urine cultures were monitored weekly to assess anti-CMV activity. Twenty-one HIV-infected persons with CD4 counts from 0 to 389 cells per l (median, 39) were enrolled in six dose-ranging groups. The first five groups enrolled four patients each to receive cidofovir infusions either weekly or biweekly for 4 weeks or every 3 weeks for 12 weeks. The sixth group enrolled one patient who received infusions of 5 mg/kg of body weight every other week. Patients receiving 0.5 or 1.5 mg/kg twice weekly experienced no serious toxicity. The first two patients who received 5 mg/kg twice weekly developed glycosuria and 2؉ proteinuria. Subsequent patients received concomitant probenecid to attempt to ameliorate renal toxicity. Seventeen patients experienced proteinuria on one or more occasions; 6 of them experienced at least 2؉ proteinuria. Four patients did not complete the study as planned because of renal toxicity. Positive CMV urine cultures reverted to negative in 2 of 8 patients receiving doses of Յ1.5 mg/kg twice weekly and 11 of 13 patients receiving higher doses. Cidofovir has in vivo anti-CMV activity demonstrated by prolonged clearing of CMV viruria, although this observation is tempered by the fact that clearance of viremia could not be demonstrated. The dose-limiting toxicity is renal; however, concurrent administration of probenecid may be protective. The maximally tolerated weekly intravenous dose with probenecid is approximately 5 mg/kg. Efficacy trials with CMV disease will define the therapeutic utility and optimal dosing interval for cidofovir.