Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Abstract

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...

Relationship between clinical and BK virological response in patients with late hemorrhagic cystitis treated with cidofovir: a retrospective study from the European Group for Blood and Marrow Transplantation

“…Therefore, the use of CDV has an intrinsic weakness because, at conventional or higher dosages, from 1 to 10 mg/kg, the peak plasma concentration of CDV is inferior to the effective concentration against BKV in vitro. 19,20 Moreover, to reduce the risk of renal tubular toxicity, probenecid is generally associated with CDV when it is used at dosage of 3-5 mg/kg every 1-2 weeks while lower doses of 1 mg/kg 1-3 times a week without probenecid was shown to be efficacious and safe in single-center series. 13,21 Esterification of CDV with lipid ester derivative (hexadecyoxypropil, octadecyloxyethil and Probenecid was used in 7 out of 7 patients.…”

Renal Transporters in Drug Development

“…In brief, probenecid inhibited the renal secretory clearance of penicillin and therefore prolonged its half-life (12). Nowadays, the coadministration of probenecid with cidofovir, an antiviral drug, is required by the FDA (13) to protect against cidofovir-mediated nephrotoxicity by inhibiting cidofovir uptake at the basolateral membrane (14,15). If a DDI were to occur at the apical membrane, the intracellular kidney References can be found in the Supplemental Material (follow the Supplemental Materials link from the Annual Reviews home page at http://www.annualreviews.org).…”

Viral Infection in the Renal Transplant Recipient

“…Low-dose cidofovir has been used to treat BK nephropathy (143)(144)(145)(146). Renal toxicity may result, especially with calcineurin inhibitors, although it is unclear how much BK infection also contributes to the renal dysfunction.…”