title: Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa.
abstract: The introduction of longer-acting erythropoietic agents into the practice of oncology has demanded an understanding of the interaction of chemotherapy with the pharmacokinetics and haematological effects of these erythropoietins. We report results of a randomised trial comparing the haematological effects of darbepoetin alfa, 6.75 mug/kg, administered once every 3 weeks to anaemic cancer chemotherapy patients on either an asynchronous (day 15) or synchronous (day 1) schedule relative to their every-3-week chemotherapy. A total of 81 patients were randomised and received the study drug (43 asynchronous; 38 synchronous). No difference was observed between groups in the primary endpoint of mean haemoglobin change after 6 weeks of therapy (P=0.45) and change scores were similar to those observed with standard weekly darbepoetin alfa therapy. In a subset of patients evaluated with intensive pharmacokinetic sampling, an increase in endogenous erythropoietin concentration (up to 4-fold) lasting approximately 1 week following chemotherapy administration was observed in both groups. Synchronous administration of darbepoetin alfa was associated with a 1.3-fold increase in the area under the darbepoetin alfa concentration-time curve compared with asynchronous administration. Our data suggest that darbepoetin alfa is effective administered every 3 weeks regardless of timing of administration with respect to chemotherapy and that receptor-mediated uptake by the erythron may be an important clearance mechanism for erythropoietic proteins.
authors.affiliation: UCLA, School of Medicine, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA 90095-6956, USA. jglaspy@mednet.ucla.edu
authors.forename: John
authors.initials: J
authors.lastname: Glaspy
authors.forename: David
authors.initials: D
authors.lastname: Henry
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.forename: Simon
authors.initials: S
authors.lastname: Tchekmedyian
authors.forename: Steve
authors.initials: S
authors.lastname: Applebaum
authors.forename: Donald
authors.initials: D
authors.lastname: Berdeaux
authors.forename: Richard
authors.initials: R
authors.lastname: Lloyd
authors.forename: Russell
authors.initials: R
authors.lastname: Berg
authors.forename: Matt
authors.initials: M
authors.lastname: Austin
authors.forename: Greg
authors.initials: G
authors.lastname: Rossi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D000068256:Darbepoetin alfa; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004921:Erythropoietin; D000068256:Darbepoetin alfa