The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats
The Lymphatic System Plays a Major Role in the Intravenous and Subcutaneous Pharmacokinetics of Trastuzumab in Rats
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DOI：
10.1021/mp400464s
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发表时间：
2014-02-01
影响因子：
4.9
通讯作者：
McIntosh, Michelle P.
中科院分区：
文献类型：
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作者：
Dahlberg, Annette M.;Kaminskas, Lisa M.;McIntosh, Michelle P.
治疗性单克隆抗体目前主要通过静脉内途径递送，因为递送治疗剂量通常需要大体积。通过皮下途径给药将具有几个治疗优势;皮下给药的抗体的吸收机制知之甚少。本研究旨在更好地了解单克隆抗体皮下吸收和转运的机制。具体而言，在SC和IV给药后，在胸淋巴管插管大鼠中探索了淋巴系统在曲妥珠单抗吸收和延长血浆暴露中的作用。在S-ADAPT中开发了群体药代动力学模型，以同时拟合所有血浆和淋巴浓度，并预测非淋巴管插管动物的药代动力学。大鼠SC给药后曲妥珠单抗的估计绝对生物利用度为85.5%。SC给药后，53.1%的曲妥珠单抗剂量通过一级过程（平均吸收时间：99.6 h）吸收至外周淋巴室，32.4%的剂量通过Michaelis Menten过程吸收至中央室。SC给药后30 h内胸淋巴液的回收率为26.7%，IV给药后为44.1%。本研究首次强调了淋巴系统在维持曲妥珠单抗长期血浆暴露中的重要作用，模型预测了SC和IV给药后该单克隆抗体在淋巴中的广泛分布。从SC注射部位到淋巴中的这种广泛的直接吸收可以实现用于治疗淋巴驻留转移性癌症的新的治疗策略。
Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly understood. This study was conducted to develop a better understanding of the mechanisms governing the subcutaneous absorption and trafficking of monoclonal antibodies. Specifically, the role of the lymphatic system in the absorption and prolonged plasma exposure of trastuzumab was explored in thoracic lymph duct-cannulated rats after SC and IV dosing. A population pharmacokinetic model was developed in S-ADAPT to simultaneously fit all plasma and lymph concentrations and to predict the pharmacokinetics in nonlymph duct-cannulated animals. The estimated absolute bioavailability of trastuzumab after SC administration in rats was 85.5%. Following SC administration, 53.1% of the trastuzumab dose was absorbed via a first-order process (mean absorption time: 99.6 h) into the peripheral lymph compartment and 32.4% of the dose was absorbed by a Michaelis Menten process into the central compartment. Recovery in thoracic lymph over 30 h was 26.7% after SC and 44.1% after IV administration. This study highlights for the first time the significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab, with the model predicting an extensive distribution of this monoclonal antibody into the lymph following SC and IV administration. This extensive direct absorption from the SC injection site into lymph may enable novel therapeutic strategies for the treatment of lymph resident metastatic cancer.