Peri- and postnatal rodent development of Hematide, an erythropoiesis-stimulating agent.
BACKGROUND
Aperi- and postnatal reproduction toxicity study was conducted in rats treated with Hematide, a synthetic PEGylated peptidic erythropoiesis stimulating agent (ESA).


METHODS
Hematide, at IV doses of 0, 0.5, 3, and 15 mg/kg, was administered from implantation through lactation on gestation days (GDs) 5 and 18 and lactation day (LD) 13.


RESULTS
Hematide induced pronounced polycythemia in all Hematide-treated dams. On LDs 2 and 21, hemoglobin (Hgb) increases above control levels were 3.1, 5.2, and 5.0 g/dL and 4.1, 5.1, and 5.5 g/dL at the 0.5, 3, and 15 mg/kg/dose, respectively. There were no effects on parturition, lactation, or maternal behavior in the F0 generation female rats. A slight decrease in pup viability on postpartum days 2-4 and lower body weights and/or body weight gain for the F1 generation were associated with pronounced polycythemia and decreases in maternal body weight gain and/or food consumption at > or =3 mg/kg/dose. Hematide fetal exposure was negligible. No Hematide effect, other than on growth and survival, was noted on developmental, functional, mating, and fertility end points in the F1 generation rats, and no effect on litter or fetal parameters was observed in the F2 generation. The maternal no-observed-adverse-effect level (NOAEL) for Hematide was 0.5 mg/kg, and the NOAEL for parturition and maternal behavior was 15 mg/kg. The NOAEL for F1 pup viability and growth was 0.5 mg/kg/dose.


CONCLUSIONS
In conclusion, the Hematide-associated adverse findings were attributed to exaggerated erythropoiesis (pronounced and prolonged polycythemia) resulting from administration of an ESA to pregnant animals.
Lewis
Elise M
EM
Charles River Laboratories, Horsham, Pennsylvania, USA.
Hoberman
Alan M
AM
Fong
Kei-Lai
KL
Schatz
Peter J
PJ
Wilson
Susan D
SD
Woodburn
Kathryn W
KW
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects / Q000196:embryology; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006397:Hematinics / Q000145:classification / Q000633:toxicity*; D007275:Injections, Intravenous; D007774:Lactation / Q000187:drug effects; D008136:Longevity / Q000187:drug effects; D008297:Male; D008425:Maternal Behavior / Q000187:drug effects; D018811:Maternal Exposure; D010455:Peptides / Q000145:classification / Q000633:toxicity*; D011086:Polycythemia / Q000139:chemically induced / Q000503:physiopathology; D011092:Polyethylene Glycols / Q000145:classification / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D012098:Reproduction / Q000187:drug effects* / Q000502:physiology; D013723:Teratogens / Q000145:classification / Q000633:toxicity*
D006397:Hematinics; D010455:Peptides; D013723:Teratogens; C514771:hematide; D011092:Polyethylene Glycols