静脉输注后，细胞周期蛋白依赖性激酶抑制剂AG-024322在食蟹猴体内的毒性和毒代动力学

Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion.

作者信息

Brown Alan P, Courtney Cynthia L, Criswell Kay A, Holliman Christopher L, Evering Winston, Jessen Bart A

机构信息

Drug Safety Research and Development, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.

出版信息

Cancer Chemother Pharmacol. 2008 Nov;62(6):1091-101. doi: 10.1007/s00280-008-0771-1. Epub 2008 May 29.

DOI:10.1007/s00280-008-0771-1

PMID:18509643

Abstract

PURPOSE

Cyclin-dependent kinases (CDKs) play a significant role in the control of cell-cycle progression and exhibit aberrant regulation in various neoplastic diseases. AG-024322 is a potent inhibitor of CDK1, CDK2, and CDK4 that produces cell-cycle arrest and antitumor activity in preclinical models. This study evaluated the toxicity of AG-024322 when given by intravenous (IV) infusion to cynomolgus monkeys, including reversibility of effects.

METHODS

Male and female monkeys received AG-024322 by 30-min IV infusion once daily for 5 days at doses of 2, 6, and 10 mg/kg (24, 72, and 120 mg/m(2), respectively). Controls received vehicle alone which was aqueous 5% dextrose, pH 3.8. Three animals/sex/group were necropsied on day 6, and two animals/sex/group at 6 and 10 mg/kg were necropsied on day 22 (reversal cohort). Doses were based upon the results of a dose range-finding study in monkeys; decreased white blood cells occurred at > or =3 mg/kg and 12 mg/kg produced central nervous system effects and was above the maximum-tolerated dose.

RESULTS

No deaths occurred and clinical signs of toxicity, including swelling at the IV administration site, were seen at > or =6 mg/kg. AG-024322 at > or =6 mg/kg produced pancytic bone marrow hypocellularity, lymphoid depletion, and vascular injury at the injection site. Renal tubular degeneration occurred at 10 mg/kg. These changes were either reversible or in a process of repair following the 17-day recovery period. Hematology changes included decreases in reticulocytes and/or granulocytes at > or =6 mg/kg, which were reversible and consistent with changes in the bone marrow. Lymphoid and bone marrow depletion are consistent with pharmacologic inhibition of CDKs by AG-024322 and were expected findings. On day 22, vacuolar degeneration of pancreatic acinar cells with increased serum amylase and lipase levels occurred in one female at 10 mg/kg. Neither sex-related differences in toxicokinetics nor plasma accumulation over 5 days of dosing were seen. Terminal phase overall mean half-life on day 5 ranged from 6.69 to 8.87 h (across dose levels) and was not dose dependent.

CONCLUSION

The no-adverse-effect dose of AG-024322 was 2 mg/kg and associated with overall mean plasma AUC(0-24.5) of 2.11 microg h/mL.

摘要

目的

细胞周期蛋白依赖性激酶（CDKs）在细胞周期进程控制中起重要作用，且在多种肿瘤性疾病中表现出异常调节。AG - 024322是一种有效的CDK1、CDK2和CDK4抑制剂，在临床前模型中可产生细胞周期停滞和抗肿瘤活性。本研究评估了静脉输注AG - 024322给予食蟹猴时的毒性，包括效应的可逆性。

方法

雄性和雌性猴子每天通过静脉输注30分钟给予AG - 024322，持续5天，剂量分别为2、6和10 mg/kg（分别为24、72和120 mg/m²）。对照组仅接受赋形剂，即pH值为3.8的5%葡萄糖水溶液。每组三只动物/性别在第6天进行尸检，每组两只动物/性别在6和10 mg/kg剂量组于第22天进行尸检（恢复组）。剂量基于猴子的剂量范围探索研究结果；白细胞减少发生在≥3 mg/kg时，12 mg/kg产生中枢神经系统效应且高于最大耐受剂量。

结果

未发生死亡，在≥6 mg/kg时可见毒性临床体征，包括静脉给药部位肿胀。≥6 mg/kg的AG - 024322导致全血细胞性骨髓细胞减少、淋巴细胞耗竭以及注射部位血管损伤。10 mg/kg时出现肾小管变性。在17天的恢复期后，这些变化要么是可逆的，要么处于修复过程中。血液学变化包括≥6 mg/kg时网织红细胞和/或粒细胞减少，这些变化是可逆的，且与骨髓变化一致。淋巴细胞和骨髓耗竭与AG - 024322对CDKs的药理抑制作用一致，是预期发现。在第22天，一只10 mg/kg剂量组的雌性猴子出现胰腺腺泡细胞空泡变性，血清淀粉酶和脂肪酶水平升高。未观察到毒代动力学方面的性别差异以及给药5天期间的血浆蓄积。第5天的终末相总体平均半衰期在6.69至8.87小时之间（跨剂量水平），且不依赖于剂量。