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 [CL(cr)] >80 mL/min), mildly impaired (CL(cr) = 50-80 mL/min), moderately impaired (CL(cr) = 30-49 mL/min), severely impaired (CL(cr) <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 CL(cr) was observed [log(CL/F) = 1.65 + 0.0062. CL(cr); r(2) = 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.
RCT Entities:
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 [CL(cr)] >80 mL/min), mildly impaired (CL(cr) = 50-80 mL/min), moderately impaired (CL(cr) = 30-49 mL/min), severely impaired (CL(cr) <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 CL(cr) was observed [log(CL/F) = 1.65 + 0.0062. CL(cr); r(2) = 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.