111In-DTPA-人表皮生长因子的临床前药代动力学、生物分布、毒理学和剂量学研究：一种用于表皮生长因子受体阳性乳腺癌的俄歇电子发射放射治疗剂

Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer.

作者信息

Reilly Raymond M, Chen Paul, Wang Judy, Scollard Deborah, Cameron Ross, Vallis Katherine A

机构信息

Division of Nuclear Medicine, University Health Network, Toronto, Ontario, Canada.

出版信息

J Nucl Med. 2006 Jun;47(6):1023-31.

PMID:16741313

Abstract

UNLABELLED

Our objective was to evaluate the pharmacokinetics, normal tissue distribution, radiation dosimetry, and toxicology of human epidermal growth factor (hEGF) labeled with (111)In ((111)In-diethylenetriaminepentaacetic acid [DTPA]-hEGF) in mice and rabbits.

METHODS

(111)In-DTPA-hEGF (3.6 MBq; 1.3 or 13 microg) was administered intravenously to BALB/c mice. The blood concentration-time data were fitted to a 3-compartment model. Acute toxicity was studied with female BALB/c mice at 42 times the maximum planned human dose (MBq/kg) or with New Zealand White rabbits at 1 times the maximum planned human dose (MBq/kg) for a phase I clinical trial. Toxicity was evaluated by monitoring body weight, by determination of hematology and clinical biochemistry parameters, and by morphologic examination of tissues. Radiation dosimetry projections in humans were estimated on the basis of the residence times in mice by use of the OLINDA version 1.0 computer program.

RESULTS

The largest amounts of radioactivity were taken up by the liver (41.3 +/- 7.8 [mean +/- SD] percentage injected dose [%ID] at 1 h after injection and decreasing to 4.9 +/- 0.3 %ID at 72 h after injection) and kidneys (18.6 +/- 0.8 %ID at 1 h and decreasing to 4.5 +/- 0.2 %ID at 72 h after injection). (111)In-DTPA-hEGF was cleared rapidly from the blood, with a half-life at alpha-phase of 2.7-6.2 min and a half-life at beta-phase of 24.0-36.3 min. The half-life of the long terminal phase could not be accurately determined. The volume of distribution of the central compartment was 340-375 mL/kg, and the volume of distribution at steady state was 430-685 mL/kg. There was no significant difference in the ratio of body weight at 15 d to pretreatment weight for mice administered (111)In-DTPA-hEGF (1.02 +/- 0.01) and mice administered unlabeled DTPA-hEGF (1.01 +/- 0.01). Erythrocyte, leukocyte, and platelet counts and serum alanine aminotransferase and creatinine levels remained in the normal ranges. No morphologic changes were observed by light microscopy in any of 19 tissues sampled. Minor morphologic changes in the liver were observed by electron microscopy. The projected whole-body dose in humans was 0.19 mSv.MBq(-1). The projected doses to the liver, kidneys, and lower large intestine were 0.76, 1.82, and 1.12 mSv.MBq(-1), respectively.

CONCLUSION

(111)In-DTPA-hEGF was safely administered to mice and rabbits at multiples of the maximum dose planned for a phase I trial in breast cancer patients.

摘要

未标记

我们的目的是评估用铟-111（¹¹¹In-二乙烯三胺五乙酸[DTPA]-人表皮生长因子[hEGF]）标记的人表皮生长因子在小鼠和兔子体内的药代动力学、正常组织分布、辐射剂量学和毒理学。

方法

将¹¹¹In-DTPA-hEGF（3.6MBq；1.3或13μg）静脉注射给BALB/c小鼠。将血药浓度-时间数据拟合为三室模型。在一项I期临床试验中，用最大计划人体剂量（MBq/kg）的42倍对雌性BALB/c小鼠进行急性毒性研究，或用最大计划人体剂量（MBq/kg）的1倍对新西兰白兔进行急性毒性研究。通过监测体重、测定血液学和临床生化参数以及对组织进行形态学检查来评估毒性。根据小鼠体内的滞留时间，使用OLINDA 1.0版计算机程序估算人体的辐射剂量学预测值。

结果

注射后1小时，肝脏摄取的放射性活度最高（41.3±7.8[平均值±标准差]注射剂量百分比[%ID]），注射后72小时降至4.9±0.3%ID；肾脏摄取的放射性活度在注射后1小时为18.6±0.8%ID，注射后72小时降至4.5±0.2%ID。¹¹¹In-DTPA-hEGF从血液中迅速清除，α相半衰期为2.7 - 6.2分钟，β相半衰期为24.0 - 36.3分钟。长终末相的半衰期无法准确测定。中央室的分布容积为340 - 375mL/kg，稳态分布容积为430 - 685mL/kg。给予¹¹¹In-DTPA-hEGF的小鼠（1.02±0.01）与给予未标记DTPA-hEGF的小鼠（1.01±0.01）在15天时的体重与预处理体重之比无显著差异。红细胞、白细胞和血小板计数以及血清丙氨酸转氨酶和肌酐水平保持在正常范围内。在采集的19个组织中，光镜下均未观察到形态学变化。电镜下观察到肝脏有轻微形态学变化。人体全身预计剂量为0.19mSv·MBq⁻¹。肝脏、肾脏和下大肠的预计剂量分别为0.76、1.82和1.12mSv·MBq⁻¹。