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Epoetin (Recombinant Human Erythropoietin)

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in Anaemia and the Stimulation of Erythropoiesis

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Summary

Synopsis

Epoetin (recombinant human erythropoietin) is a sialoglycoprotein hormone that appears to be immunologically and biologically equivalent to the endogenous compound, enhancing erythropoiesis dose-proportionally. The therapeutic efficacy of epoetin in thetreatment of anaemia associated with chronic renal failure has been established, with almost all patients responding with increases in haematocrit and haemoglobin levels, and improvements in quality of life. Some patients demonstrate relative epoetin resistance and require a higher dosage to achieve target haemoglobin and haematocrit levels.

Maintenance of an adequate iron supply is essential and iron supplementation is recommended if serum ferritin is below 100 to 150 μg/L or transferrin saturation is less than 20%. The incidence of serious adverse effects may be reduced by maintaining a moderate rate of increase in the haematocrit with close monitoring of blood pressure and dialysis efficacy. Individual titration of epoetin dosage is recommended, with increases made in small increments to achieve haematocrit and haemoglobin levels of 30 to 33% and 10 to 12 g/dl, respectively, although the optimal haematocrit for each patient should be individually determined. Some patients will also require a modest increase in heparin dosage because of a possible increase in clotting tendency. Hypertension is the most common adverse effect in patients with chronic renal failure, occurring partially as a result of increasing blood viscosity and peripheral vascular resistance with the correction of anaemia. Maintenance epoetin therapy has been given for more than 2 years without a decrease in responsiveness and does not appear to adversely affect the outcome of renal transplantation.

Thus, epoetin represents a significant therapeutic advance in the treatment of anaemia associated with chronic renal failure and should be considered a first option for these patients. Its potential value in the treatment of anaemia associated with other disorders and in facilitating autologous blood donation remains to be fully determined.

Pharmacodynamic Studies

Epoetin (recombinant human erythropoietin) stimulates proliferation and differentiation of committed erythroid progenitors dose-proportionally, with increases in reticulocyte count followed by rises in haematocrit and haemoglobin levels. In chronic haemodialysis patients red cell mass also increases but cell lifespan may remain considerably reduced. Tissue iron stores are mobilised during epoetin therapy, and iron supplementation to maintain erythropoiesis is recommended when serum ferritin is < 100 to 150 μg/L and/or transferrin saturation is < 20%; therapy has also been associated with modest increases in platelet and monocyte counts in some studies although these remain within normal limits. A reduction in bleeding times and improved platelet function have been correlated with rises in haematocrit in epoetin recipients receiving chronic haemodialysis, suggesting an improvement in the haemostatic defect found in these patients.

Blood pressure may increase in epoetin recipients, particularly during induction therapy; however, limited evidence suggests that during maintenance epoetin therapy, some degree of haemodynamic adaptation to the increased haematocrit may occur. Improvements in left ventricular function and cardiac output appear to be less likely in patients with preexisting hypertension or in those who develop hypertension during epoetin therapy. Treatment of anaemic predialysis patients with epoetin has been successful, with improvements in exercise capacity similar to those observed in chronic haemodialysis patients, and although limited studies in animal models have suggested epoetin therapy may accelerate the progression of chronic renal failure, this has not been found clinically.

Pharmacokinetic Studies

The pharmacokinetics of epoetin when administered by intravenous, subcutaneous or intraperitoneal routes have been investigated, although published studies to date have been limited. Peak serum concentrations are observed immediately after intravenous epoetin administration, with concentrations of 3000 to 5000 mU/ml reported after single doses of 150 U/kg. Intravenous epoetin has a half-life of about 8 to 10 hours in chronic haemodialysis patients following single dose administration but this decreases to about 6 hours with repeated doses. In predialysis patients, the half-life of epoetin following repeated intravenous administration may be slightly reduced compared with that in patients receiving chronic haemodialysis.

Peak serum concentrations are achieved 5 to 18 hours after subcutaneous epoetin administration and are maintained for several hours. There appears to be no difference in pharmacodynamic effects compared with intravenous administration despite the reduced bioavailability of subcutaneously administered drug. The pharmacokinetics of epoetin after intraperitoneal administration require further investigation. Although the sites of metabolism have not been established, evidence suggests the majority of a dose of epoetin is hepatically eliminated. Renal excretion plays a small role with up to 10% of erythropoietin excreted unchanged in the urine of normal volunteers.

Therapeutic Trials

Epoetin has been primarily investigated in short term uncontrolled trials as a treatment for anaemia associated with chronic renal failure in haemodialysis patients. Almost all patients have responded, with initial increases in haematocrit observed within 1 to 3 weeks and the rate of rise being dose proportional. Target haematocrit levels, which have varied between 30 and 40% in different studies, may be achieved within 4 to 6 weeks. Improvements in patient quality of life have included improved exercise tolerance, mood, sleep/wake patterns and sexual function. In controlled studies, epoetin recipients have shown significant increases in haematocrit and haemoglobin levels compared with pretreatment levels and with similar patients receiving androgen therapy, placebo or no treatment.

Long term maintenance therapy remains to be fully evaluated but, in the experience reported to date, loss of responsiveness has not been observed and confirmed adverse effects on the outcome of renal transplantation have not been reported. Although most studies have used intravenous administration, subcutaneous and intraperitoneal routes also appear effective. Studies in patients with anaemia associated with chronic renal failure not requiring dialysis indicate that epoetin is also beneficial in this situation. Epoetin is also being evaluated for the treatment of anaemia associated with the acquired immune deficiency syndrome (AIDS), rheumatoid arthritis, prematurity, Gaucher’s disease, in sickle cell anaemia and in autologous blood donation.

Adverse Effects

Hypertension, occasionally with associated seizures, appears to be the major adverse effect in patients with chronic renal failure, and blood pressure should be closely monitored with prompt institution or dose adjustment of antihypertensive therapy as required. Vascular thrombotic events, particularly at dialysis access sites, have also been noted in epoetin recipients and some patients require a modest increase in heparin dosage. The incidence of cardiovascular and thrombotic adverse events directly attributable to epoetin therapy has not been fully determined, but does not appear to be above background levels in patients with chronic renal failure. Changes in electrolyte levels before dialysis have also been observed but adverse sequelae may be largely avoided by maintaining dialysis efficacy and dietary compliance. Other serious adverse effects are relatively uncommon. Significant cardiovascular or thrombotic adverse events associated with epoetin therapy were not observed in AIDS patients with anaemia associated with zidovudine (azidothymidine) therapy or in patients receiving epoetin to facilitate blood donation for later autologous transfusion.

Dosage and Administration

Although dosage is determined primarily by patient response, it is recommended that a relatively low epoetin dosage be employed initially (for example 50 to 100 U/kg intravenously 3 times weekly), increasing in small increments if significant rises in reticulocyte count, haematocrit and/or haemoglobin levels are not observed within 4 weeks. Epoetin dosage should be reduced if the haematocrit increases more than 4 points in any 2-week period. A target haematocrit of 30 to 33% and/or a target haemoglobin level of 10 to 12 g/dl is suggested, with maintenance therapy adjusted accordingly. However, the optimal haematocrit level for each patient should be determined individually. Epoetin is usually administered at the end of each dialysis session in long term haemodialysis patients.

Subcutaneous epoetin administration appears to maintain target haemoglobin/haematocrit values at a dosage similar to that required intravenously, and may become the administration route of choice, particularly in patients not receiving haemodialysis. Intraperitoneal administration appears to require dosages similar to, or greater than, those used intravenously. Relative resistance to epoetin has been observed in patients with reduced iron stores, or with aluminium intoxication, osteitis fibrosa, infection or inflammation, but is usually overcome with iron supplementation or dosage increases, respectively.

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Various sections of the manuscript reviewed by: R.R. Bailey, Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand; W.M, Bennett, Division of Nephrology and Hypertension, Oregon Health Sciences University, Portland, Oregon, USA; M. V. Berridge, Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington,New Zealand; J. Bommer, University of Heidelberg, Department of Internal Medicine, Heidelberg, Federal Republic of Germany; CD. Brown, Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA; L.A.M. Frenken, Department of Medicine, Division of Nephrology, University Hospital Nijmegen, Nijmegen, The Netherlands; K.L. Lynn, Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand; R.A. Robson, Department of Nephrology, Christchurch Hospital, Christchurch, New Zealand; R.M. Schaefer, Department of Internal Medicine, Division of Nephrology, University of Wurzburg, Wurzburg, Federal Republic of Germany; J.L. Spivak, Johns Hopkins University Hospital, Division of Hematology, Baltimore, Maryland, USA; WJ. Stone, Nephrology Medical Service, Veterans Administration Medical Center, South Nashville, Tennessee, USA; A. Urabe, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan; CG, Winearls, Renal Unit, Department of Medicine, Churchill Hospital, Headington, Oxford, England; C Zehnder, Kantonsspitals, Med Klin, Nephrol Abt, Aarau, Switzerland.

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Faulds, D., Sorkin, E.M. Epoetin (Recombinant Human Erythropoietin). Drugs 38, 863–899 (1989). https://doi.org/10.2165/00003495-198938060-00004

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