Clinical pharmacokinetics of cidofovir in human immunodeficiency virus- infected patients

K. C. Cundy, B. G. Petty, J. Flaherty, P. E. Fisher, M. A. Polis, M. Wachsman, P. S. Lietman, J. P. Lalezari, M. J.M. Hitchcock, H. S. Jaffe

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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.

Original languageEnglish (US)
Pages (from-to)1247-1252
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume39
Issue number6
DOIs
StatePublished - Jan 1 1995

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Cundy, K. C., Petty, B. G., Flaherty, J., Fisher, P. E., Polis, M. A., Wachsman, M., Lietman, P. S., Lalezari, J. P., Hitchcock, M. J. M., & Jaffe, H. S. (1995). Clinical pharmacokinetics of cidofovir in human immunodeficiency virus- infected patients. Antimicrobial agents and chemotherapy, 39(6), 1247-1252. https://doi.org/10.1128/AAC.39.6.1247