title: Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin after single and multiple subcutaneous doses to healthy subjects.
abstract: OBJECTIVE
  To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration.
  
  
  METHODS
  Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in 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, randomized placebo-controlled studies in healthy volunteers.
  
  
  RESULTS
  The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose-dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage 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 baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa.
  
  
  CONCLUSIONS
  These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. 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.
authors.affiliation: Department of Drug Metabolism, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869-0602, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Cheung
authors.forename: B L
authors.initials: BL
authors.lastname: Goon
authors.forename: M C
authors.initials: MC
authors.lastname: Guilfoyle
authors.forename: M C
authors.initials: MC
authors.lastname: Wacholtz
mesh_terms: D000328:Adult; D019540:Area Under Curve; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005293:Ferritins / Q000097:blood; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D007501:Iron / Q000008:administration & dosage / Q000097:blood; D008297:Male; D011994:Recombinant Proteins; D012016:Reference Values; D017701:Reticulocyte Count / Q000187:drug effects
chemical_list: D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D005293:Ferritins; D007501:Iron