PHARMACOKINETICS AND PHARMACODYNAMICS OF RECOMBINANT-HUMAN-ERYTHROPOIETIN AFTER SINGLE AND MULTIPLE SUBCUTANEOUS DOSES TO HEALTHY-SUBJECTS

Objectives: To understand the pharmacokinetic and pharmacodynamic prop erties of recombinant human erythropoietin (epoetin alfa) and to conti nue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated admin istration. Methods: Epoetin alfa was administered as single subcutaneo us doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and i n multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open-label, randomi zed placebo-controlled studies in healthy volunteers. Results: The abs orption rate of epoetin alfa after subcutaneous administration was ind ependent of dose, whereas clearance was dose-dependent in that it decr eased with increasing dose. There was a linear relationship between re sponse measured as percentage of reticulocytes area under the curve (A UC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond t he 1800 IU/kg dose, there was a saturation of response. The mean perce ntage of reticulocytes after single-dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to b aseline values by day 22. In contrast, the mean percentage of reticulo cytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustaine d increases in percentage of reticulocytes (1% to 2%). The mean percen tage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticu locytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily o ral iron supplementation was given, mean serum ferritin levels decline d by approximately 75% through day 22 in subjects treated with multipl e doses of epoetin alfa. Conclusions: These findings show that the pha rmacologic response to epoetin alfa is a function of dose and dosing r egimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.