Kinetics of haematopoietic recovery after dose-intensive chemo/radiotherapy in mice: optimized erythroid support with darbepoetin alpha.
Despite its frequency and impact on clinical outcomes, anaemia in cancer patients remains poorly understood and suboptimally treated. The definition of optimum treatment schedules with erythropoietic agents requires a suitable model of chemotherapy-induced progressive anaemia. This study investigated novel strategies such as once-per-chemotherapy-cycle dosing, synchronization between erythroid supportive care and chemotherapy, and definition of the optimum timing of erythroid support. A murine model of carboplatin chemotherapy/radiotherapy (CRT)-induced anaemia was used, which caused progressive anaemia across multiple cycles. Weekly administration of recombinant human erythropoietin (rHuEPO) was effective, but the longer-acting darbepoetin alpha resulted in superior responses. In all animals, anaemia became progressive and more refractory across cycles because of accumulated bone marrow damage. Exploiting a specific enzyme-linked immunosorbent assay, which could distinguish between darbepoetin alpha and endogenous erythropoietin, the effect of CRT upon the pharmacokinetics of darbepoetin alpha showed that clearance of darbepoetin alpha, and presumably erythropoietin, was at least partially dependent on a chemotherapy-sensitive pathway. Scheduling data suggested that administration of erythropoietic agents prior to chemotherapy was more effective than administration after chemotherapy. There was no evidence that erythropoietic agents exacerbated anaemia, even when administered immediately prior to CRT in an attempt to "prime" erythroid cells for the effects of CRT.
Hartley
Cynthia
C
Departments of Hematology Research and Pharmacokinetics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Elliott
Steve
S
Begley
C Glenn
CG
McElroy
Patricia
P
Sutherland
Weston
W
Khaja
Raheem
R
Heatherington
Anne C
AC
Graves
Tom
T
Schultz
Henry
H
Del Castillo
Juan
J
Molineux
Graham
G
D000740:Anemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016190:Carboplatin / Q000009:adverse effects; D003131:Combined Modality Therapy; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D006454:Hemoglobins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011832:Radiation Injuries / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D011878:Radiotherapy / Q000009:adverse effects; D011994:Recombinant Proteins
D000970:Antineoplastic Agents; D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D016190:Carboplatin