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Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency
Marion Haubitz1, Frank Bohnenstengel, Reinhard Brunkhorst
1Department of Nephrology, University Medical School Hannover, Hannover, Germany. Haubitz.Marion@Mh-Hannover.de
Background:
Intravenous pulse administration of cyclophosphamide (CYC) has been successfully used for the treatment of various autoimmune diseases. These patients often present with impaired renal function or even end-stage renal failure. Nevertheless, data concerning pharmacokinetics of CYC in renal insufficiency (RI) and on hemodialysis (HD) are rare and contradictory.
Methods:
The pharmacokinetics of CYC (0.5 to 1 g/m2 as a one-hour infusion) were determined in patients with renal involvement of autoimmune diseases. Group A (N = 6) patients had a creatinine clearance (CCr) of 25 to 50 mL/min, group B patients' (N = 5) CCr was 10 to 24 mL/min, and group C (N = 6) patients had CCr values <10 mL/min and HD. Concentrations of CYC in serum, dialysate and urine were measured by HPLC. Twelve previously investigated patients with normal renal function served as controls.
Results:
Mean clearance (CL) of CYC was significantly reduced with decreased renal function (79 vs. 57 and 47 mL/min, controls vs. A and B, respectively, P < 0.05), but only moderately lower in the patients who received a three-hour HD during the study period (group C, 64 mL/min, NS). This resulted in reciprocal increases in systemic drug exposure (dose corrected AUC was 216, 298, 382 and 266 microg x h/mL x g, controls, A, B and C, respectively). Urinary excretion of CYC was markedly reduced in all patients with RI (renal CL was 14.9 vs. 3.4, 2.4 and 2.1 mL/min, controls vs. A, B and C, respectively, P < 0.001). However, in patient group C, a mean of 22% of administered CYC dose was eliminated by a three hour HD starting seven hours after CYC administration. Individual CCr values were significantly (P < 0.001) correlated with renal and systemic CL of CYC, respectively, and negatively correlated with dose corrected AUC.
Conclusions:
Clearance of CYC is decreased in patients with reduced renal function, thereby resulting in an increased systemic drug exposure. However, in hemodialysis-dependent patients, removal of CYC into the dialysate has to be taken into account. For optimal dosing of CYC in patients with renal insufficiency, the severity of renal impairment and the use and timing of hemodialysis have to be considered.