The pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in haemodialysis patients.
1. The pharmacokinetics of and therapeutic response to recombinant human erythropoietin (rcEPO) were studied in 12 patients under chronic haemodialysis on a thrice weekly intravenous rcEPO treatment scheme. The kinetics of rcEPO were also assessed after a subcutaneous injection during the initial period and during maintenance treatment. RcEPO was measured in plasma by radioimmunoassay. 2. After the first i.v. dose plasma erythropoietin concentrations were best described by a monoexponential disposition function with a mean (+/- s.d.) elimination half-life of 5.4 +/- 1.7 h. The volume of distribution was 70 +/- 5.2 ml kg-1 and the clearance was 10.1 +/- 3.5 ml h-1 kg-1 (n = 12). 3. After 3 months of continuous therapy, the plasma half-life of rcEPO decreased by 15% (P < 0.05, mean half-life during steady state: 4.6 +/- 2.8 h), while mean clearance and volume of distribution remained constant. 4. After the first s.c. injection the mean (+/- s.d.) absorption time was 22 +/- 11 h and systemic availability was 44 +/- 7%. 5. Changes in haemoglobin concentrations were described by a linear additive dose-response model, defined by an efficacy constant (Keff) and the mean erythrocyte lifetime (MRTHb). The sample mean (+/- s.d.) Keff was 0.043 +/- 0.017 g dl-1 Hb per 1000 units rcEPO and MRTHb was 10.02 +/- 1.75 weeks. The net effect of rcEPO treatment was described by the area under the unit-dose-response curve (AUEC) with a mean (+/- s.d.) value of 0.45 +/- 0.23 g dl-1 weeks. 6. RcEPO clearance showed a significant positive correlation (r2 = 0.41) with the effectiveness of rcEPO therapy, as measured by the parameters Keff or AUEC.
Brockmöller
J
J
Institute of Clinical Pharmacology, Klinikum Steglitz, Free University Berlin, Germany.
Köchling
J
J
Weber
W
W
Looby
M
M
Roots
I
I
Neumayer
H H
HH
D000328:Adult; D000368:Aged; D004906:Erythrocyte Count / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006435:Renal Dialysis; D012156:Reticulocytes / Q000187:drug effects
D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin