Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis

Background: Cidofovir is an antiviral agent used for the treatment of cytom egalovirus infection in patients with acquired immunodeficiency syndrome. B ecause cidofovir is primarily eliminated by the kidneys and because its mai n adverse effect is nephrotoxicity, an understanding of the pharmacokinetic disposition of cidofovir in patients with renal insufficiency is necessary . Methods: Twenty-four subjects were enrolled into this study and were divide d into 6 groups depending on their degree of renal dysfunction, including s ubjects receiving maintenance continuous ambulatory peritoneal dialysis and high-flux hemodialysis. The creatinine clearance (CLCR) for subjects not r eceiving dialysis ranged from 12 to 164 mL/min, Each subject received a sin gle 0.5 mg/kg intravenous dose of cidofovir over 1 hour. Subjects not recei ving dialysis were given intravenous hydration with 1 L normal saline solut ion and concomitant oral probenecid. Serial serum and urine samples were co llected to determine pharmacokinetic parameters with use of noncompartmenta l methods. Results: Mean +/- SD cidofovir clearance (CL) in control subjects (normal r enal function; n = 5) was 1.7 +/- 0.1 mL/min/kg, which decreased with decli ning renal function as indicated by the regression equation: CL (mL/min/kg) = 0.94 x CLCR (mL/min/kg) + 0.064 (r(2) = 0.91). Mean volume of distributi on at steady state did not change significantly in subjects with kidney dis ease and cidofovir serum elimination half-life was significantly increased in subjects with severe renal impairment. Cidofovir was not significantly c leared during continuous ambulatory peritoneal dialysis, but high-flux hemo dialysis resulted in the removal of 52% +/- 11% of the dose administered, Conclusion: The significant (P < .001) correlation observed between CLCR an d CL in subjects with varying degrees of renal insufficiency indicates that aggressive dosage reduction of cidofovir would be necessary in subjects wi th kidney disease to ensure comparable drug exposure based on serum levels.