Pharmacokinetics of anakinra in subjects with different levels of renal function.

Objective Our objective was to assess the effects of decreased renal function and dialysis on anakinra pharmacokinetics. Methods In 2 separate studies anakinra (1 mg/kg) was given intravenously to 12 healthy subjects and 20 subjects with end-stage renal disease undergoing dialysis. In a third study anakinra (100 mg) was given subcutaneously to 30 subjects who had been assigned to 5 groups according to renal function, as follows: normal (creatinine clearance [CLcr] >80 mL/min), mildly impaired (CLcr = 50-80 mL/min), moderately impaired (CLcr = 30-49 mL/min), severely impaired (CLcr <30 mL/min), and end-stage renal disease undergoing hemodialysis. Plasma samples were collected up to 96 hours after dosing for anakinra measurement by enzyme-linked immunoassay. Results The mean plasma clearance (CL) of anakinra after intravenous administration was reduced from 137 ± 21 mL/min in the healthy subjects to approximately 20 mL/min for the subjects with end-stage renal disease (P < .0001). The removal of anakinra by dialysis was less than 2.5% of the dose administered. Compared with mean anakinra clearance (CL/F) after subcutaneous administration in the group with normal renal function (170 ± 37 mL/min), CL/F was reduced by 16% in the mildly impaired group (142 ± 59 mL/min), by 50% in the moderately impaired group (84.5 ± 24.7 mL/min, P < .05), by 70% in the severely impaired group (51.5 ± 8.4 mL/min, P < .05), and by 75% in the group with end-stage renal disease (42.7 ± 4.7 mL/min, P < .05). A significant correlation between anakinra CL/F and CLcr was observed [log(CL/F) = 1.65 + 0.0062 · CLcr; r2 = 0.718]. Conclusion Anakinra is predominantly cleared renally in humans; the plasma clearance of anakinra decreased with decreasing renal function. The dialysis process has a minimal effect on the removal of anakinra. Our results suggest that a dose or schedule adjustment is indicated for persons with severe renal impairment or end-stage renal disease. Clinical Pharmacology & Therapeutics (2003) 74, 85–94; doi: 10.1016/S0009-9236(03)00094-8