Evaluation of the developmental toxicity of lenalidomide in rabbits.
BACKGROUND
Lenalidomide, a thalidomide analog, is indicated for treatment of patients with deletion-5q myelodysplastic syndromes or multiple myeloma. NZW rabbits were used because of sensitivity to thalidomide's teratogenicity.


METHODS
Range-finding and pulse-dosing studies preceded a full developmental toxicity study in New Zealand white (NZW) rabbits (25/group) given lenalidomide (0, 3, 10, or 20 mg/kg/day) or thalidomide (180 mg/kg/day) by stomach tube on gestation days (GD) 7-19. Clinical signs, body weights, and feed consumption were recorded daily from GD 7. On GD 29, standard maternal necropsy, uterine content, and fetal evaluations were carried out.


RESULTS
In all studies, thalidomide was selectively toxic to development. In the pulse-dosing study, lenalidomide did not affect development at 100 mg/kg/day. Increases in C(max) and AUC(0-24 hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification). Thalidomide selectively reduced fetal body weight, increased postimplantation loss and caused characteristic limb and other dysmorphology.


CONCLUSIONS
The maternal and developmental NOAELs for lenalidomide are 3 mg/kg/day. Unlike thalidomide, lenalidomide affected embryo-fetal development only at maternally toxic dosages, confirming that structure-activity relationships may not predict maternal or developmental effects. No fetal malformations were attributable to lenalidomide.
Christian
Mildred S
MS
Argus International, Horsham, Pennsylvania 19044, USA. mschristian@comcast.net
Laskin
Oscar L
OL
Sharper
Valerie
V
Hoberman
Alan
A
Stirling
David I
DI
Latriano
Louise
L
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D005333:Fetus / Q000187:drug effects; D000077269:Lenalidomide; D011247:Pregnancy; D011817:Rabbits; D013723:Teratogens / Q000633:toxicity; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
D013723:Teratogens; D013792:Thalidomide; D000077269:Lenalidomide