title: Pharmacokinetics of low-dose cidofovir in kidney transplant recipients with BK virus infection.
abstract: BACKGROUND
  BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen are not known in kidney transplant recipients.
  
  
  METHODS
  We investigated the pharmacokinetics (PK) of low-dose cidofovir (0.24 - 0.62 mg/kg) both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design.
  
  
  RESULTS
  The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m(2) (range: 17-75 mL/min/1.73 m(2) ). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir PK. Maximum cidofovir plasma concentrations, which averaged approximately 1 μg/mL, were significantly below the 36 μg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P > 0.05).
  
  
  CONCLUSIONS
  Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r(2) = 0.8 without probenecid; r(2) = 0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships to optimize the cidofovir dosing regimen for BKV infection.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Momper
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: R
authors.initials: R
authors.lastname: Shapiro
authors.forename: K S
authors.initials: KS
authors.lastname: Schonder
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: P S
authors.initials: PS
authors.lastname: Randhawa
authors.forename: R
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001739:BK Virus / Q000187:drug effects*; D000077404:Cidofovir; D018592:Cross-Over Studies; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism* / Q000821:virology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000493:pharmacokinetics*; D027601:Polyomavirus Infections / Q000378:metabolism*; D011339:Probenecid / Q000493:pharmacokinetics; D014412:Tumor Virus Infections / Q000378:metabolism*; D014766:Viremia / Q000378:metabolism
chemical_list: D000277:Adjuvants, Pharmaceutic; D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir; D011339:Probenecid