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The impact of timing of chemotherapy relative to darbepoetin alfa (DA) on DA pharmacokinetics (PK) and hematologic effects
Author(s) -
Heatherington A. C.,
Henry D.,
Patel R.,
Tchekmedyian N. S.,
Berg R.,
Austin M.,
Rossi G.,
Glaspy J.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.227
Subject(s) - pharmacokinetics , dosing , medicine , chemotherapy , pharmacology , gastroenterology
DA is usually administered synchronously with chemotherapy (ctx). This study evaluated whether timing of DA dosing, relative to ctx, impacted its PK and efficacy. The study was conducted in anemic cancer patients receiving ctx once every 3 weeks (Q3W), randomized to receive DA 6.75 μg/kg Q3W either 1 week before ctx (asynchronous) or on the same day as ctx (synchronous) for up to 16 weeks. The effects of cyclic ctx on PK of DA and endogenous EPO levels were evaluated in a sub‐set of patients after 1 st dose. 81 patients were randomized to receive study drug. Synchronous dosing resulted in higher maximal DA concentrations (mean ± SD) (26.5 ± 9.67 ng/mL, n=13) than asynchronous dosing (15.5 ± 5.25 ng/mL, n=12), with a 1.6‐fold increase in exposure (AUC) over week 1. However, DA concentrations increased between 7‐10 days post‐dose due to ctx administration at day 7 for the asynchronous group, resulting in a 1.4‐fold greater AUC for wks 2 and 3. DA terminal half‐life tended to be longer in the asynchronous group (87.7 ± 26.0 hr vs 60.9 ± 22.3 hr). In both groups, EPO was elevated for 1 week after ctx, with peak concentrations (4‐5‐fold increase) at 48 hr. Despite the PK differences, mean (95% CI) change in hgb at wk 7 was similar [0.95 (0.56, 1.33) g/dL vs 1.03 (0.58, 1.47) g/dL]. These results show that DA dosed once per cycle is effective in treating chemotherapy‐induced anemia. The findings also indicate that the bone marrow may play a role in the clearance of these agents. Clinical Pharmacology & Therapeutics (2004) 75 , P60–P60; doi: 10.1016/j.clpt.2003.11.227