Evaluation of the developmental toxicity of lenalidomide in rabbits.

Abstract

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.

• Authors: Mildred S Christian, Oscar L Laskin, Valerie Sharper, Alan Hoberman, David I Stirling, Louise Latriano
• Journal: Birth defects research. Part B, Developmental and reproductive toxicology (Birth Defects Res B Dev Reprod Toxicol) Vol. 80 Issue 3 Pg. 188-207 (Jun 2007) ISSN: 1542-9733 [Print] United States
• PMID: 17570132 (Publication Type: Journal Article)
• Copyright: Copyright 2007 Wiley-Liss, Inc.

Chemical References

• Teratogens
• Thalidomide
• Lenalidomide

Topics

• Abnormalities, Drug-Induced (etiology)
• Animals
• Embryonic Development (drug effects)
• Female
• Fetal Death (chemically induced)
• Fetus (drug effects)
• Lenalidomide
• Pregnancy
• Rabbits
• Teratogens (toxicity)
• Thalidomide (administration & dosage, analogs & derivatives, toxicity)