Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Cancer Chemother Pharmacol. 2013 May;71(5):1219-29. doi: 10.1007/s00280-013-2116-y. Epub 2013 Mar 3.
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions.
Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach.
PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib.
The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.
依维莫司是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，已被批准作为免疫抑制剂以及肝癌（HCC）和肾细胞癌（RCC）的二线治疗药物。索拉非尼是一种多激酶抑制剂，用于 HCC 和 RCC 的一线治疗。本研究评估了依维莫司和索拉非尼单独及联合在血浆和组织中的药代动力学（PK），在小鼠中建立了基于生理学的药代动力学（PBPK）模型，并评估了 PK 药物相互作用的可能性。
在 7 项不同的研究中，单独及联合给予免疫功能正常的雄性小鼠和严重联合免疫缺陷（SCID）小鼠单次和多次口服依维莫司和索拉非尼，并在这些小鼠中植入低传代的患者来源胰腺腺癌。在 24 小时内采集血浆和组织样本（包括肿瘤），并通过液相色谱-串联质谱法（LC-MS/MS）进行分析。依维莫司和索拉非尼向脑、肌肉、脂肪、肺、肾、胰腺、脾、肝、胃肠道和肿瘤的分布被建模为灌注速率限制，并使用群体方法同时拟合来自不同研究的数据。
建立了依维莫司和索拉非尼的 PBPK 模型。PBPK 分析表明，联合使用两种药物的 PK 与单独使用每种药物的 PK 相同。索拉非尼剂量增加两倍会使肿瘤暴露增加十倍，这表明转运体参与了索拉非尼在肿瘤中的沉积。
所开发的 PBPK 模型表明这两种药物在小鼠体内不存在 PK 相互作用。这些研究为这些药物在患者来源的原发性胰腺腺癌原代培养物中的药效学评估提供了依据。
