Evaluation of the developmental toxicity of lenalidomide in rabbits
Evaluation of the developmental toxicity of lenalidomide in rabbits
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DOI：
10.1002/bdrb.20115
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发表时间：
2007-06-01
影响因子：
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通讯作者：
Latriano, Louise
中科院分区：
文献类型：
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作者：
Christian, Mildred S.;Laskin, Oscar L.;Latriano, Louise
背景：来那度胺是一种沙利度胺类似物，适用于治疗 5q 缺失骨髓增生异常综合征或多发性骨髓瘤患者。由于对沙利度胺的致畸性敏感，因此使用 NZW 兔。方法：在对新西兰白兔（NZW）（25 只/组）进行全面发育毒性研究之前，在妊娠第 7-19 天通过胃管给予来那度胺（0、3、10 或 20 mg/kg/天）或沙利克胺（180 mg/kg/天）进行范围探索和脉冲剂量研究。从第 7 天开始每天记录临床体征、体重和饲料消耗。第 29 天，进行标准母体尸检、子宫内容物和胎儿评估。结果：在所有研究中，沙利度胺对发育都有选择性毒性。在脉冲给药研究中，来那度胺 100 毫克/公斤/天不会影响发育。来那度胺的 C-max 和 AUC（0-24 小时）值的增加略小于剂量比例；来那度胺发生在胎儿身上。 10 和 20 毫克/公斤/天时，来那度胺具有母体毒性（体重增加和饲料消耗减少；20 毫克/公斤/天时，体重减轻和 1 例流产）。 10 和 20mg/kg/天的发育毒性包括胎儿体重减轻、植入后损失增加和胎儿变异（发病/皮肤变紫、中间肺叶不发育、鼻额缝不规则和掌骨骨化延迟）。沙利度胺选择性地降低胎儿体重，增加植入后损失并导致特征性肢体和其他畸形。结论：来那度胺的母体和发育 NOAEL 为 3mg/kg/天。与沙利度胺不同，来那度胺仅在母体毒性剂量下影响胚胎-胎儿发育，这证实结构-活性关系可能无法预测母体或发育影响。没有因来那度胺导致胎儿畸形。
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 thaliclomide (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 100mg/kg/day. Increases in C-max and AUC(0-24hr) values for lenalidomide were slightly less than dose-proportional; lenalidomide occurred in the fetuses. At 10 and 20mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20mg/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 3mg/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.