Clinical Pharmacology and Economics of Recombinant Human Erythropoietin in End-Stage Renal Disease : The Case for Subcutaneous Administration 1
The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoietin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 ± 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 ± 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 ± 10 U/kg. The other 16 patients required 137 ± 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t#{189}of 6.8 ± 0.3 h). Single i.v. doses >150 U/kg were required to increase basal erythropoietin by 30 mU/ 1 Received January 30, 1991. Accepted October 29, 1991. 2 Correspondence to Dr. A. Besarab, Room 1028A College Building, Division of Nephrology, Department of Medicine. 1015 Walnut Street. Philadelphia, PA 19107. 1046-6673/0209-1405$03.00/0 Journal of the American Society of Nephrology Copyright C 1992 by the American Society of Nephrology ml at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that iv. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of I I 0 to I 20 U/kg is effective treatment of anemia in most dialysis patients.