title: Pharmacokinetic and pharmacodynamic considerations on the erythropoietin effect and adverse events of darbepoetin.
abstract: BACKGROUND
  In the TREAT and RED-HF trials, patients who received a high darbepoetin dose had an increased risk of adverse events. To find an explanation, the published literature was analyzed on the pharmacokinetics and pharmacodynamics of darbepoetin.
  
  
  METHODS
  Based on the sigmoid Emax model, the concentration producing 50% of the maximum erythropoietin effect is reported as CE50 = 0.41 ng/ml and the Hill coefficient as H = 3.0 for darbepoetin. Accordingly, a pharmacodynamics-based threshold concentration can be estimated with CE05 = 0.153 ng/ml producing 5% of Emax and a ceiling concentration with CE95 = 1.098 ng/ml producing 95% of Emax, respectively.
  
  
  CONCLUSIONS
  Darbepoetin trough levels should not be less than the threshold concentration but peak levels above the ceiling concentration could be associated with an increased risk of adverse events. The time span associated with the concentration fluctuation between the ceiling and the threshold concentration is estimated with 236 h (= 2.84 times elimination half-life of 83 h) and shorter than the 336 h when dosing every other week. According to such time-dependent pharmacodynamics, a weekly dosing regimen might be more effective and associated with less adverse events than higher doses every other week in patients with suboptimal response to a normal darbepoetin dose.
authors.affiliation: University Hospital, Center for Internal Medicine, Department Innere 1, Nephrology , Albert-Einstein-Allee 23, D-89070 Ulm , Germany +49 731 500 44561 ; +49 731 500 44567 ; frieder.keller@uni-ulm.de.
authors.forename: Frieder
authors.initials: F
authors.lastname: Keller
authors.forename: Ulla
authors.initials: U
authors.lastname: Ludwig
authors.forename: David
authors.initials: D
authors.lastname: Czock
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000378:metabolism; D002986:Clinical Trials as Topic / Q000379:methods; D000068256:Darbepoetin alfa; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D016896:Treatment Outcome
chemical_list: D004921:Erythropoietin; D000068256:Darbepoetin alfa
keywords: Hill coefficient; ceiling concentration; darbepoetin; pharmacodynamics; pharmacokinetics; threshold concentration; time-dependent action