Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.
Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.
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DOI：
10.1371/journal.pone.0142845
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Koch KM
中科院分区：
文献类型：
--
作者：
Spector NL;Robertson FC;Bacus S;Blackwell K;Smith DA;Glenn K;Cartee L;Harris J;Kimbrough CL;Gittelman M;Avisar E;Beitsch P;Koch KM
癌症治疗从细胞毒性药物到肿瘤靶向治疗的范式转变提出了新的挑战，包括基于生物有效剂量而不是历史最大耐受剂量来优化剂量和时间表。目前，最佳剂量的确定是使用血浆中酪氨酸激酶抑制剂的浓度作为肿瘤浓度的替代。为了检验这种血浆-肿瘤关系，我们探索了拉帕替尼在小鼠和人类肿瘤和血浆中的水平之间的联系，以及这些因素对人类肿瘤中人表皮生长因子受体(HER)磷酸化的影响。携带BT474HER2+人乳腺癌移植瘤的小鼠每天给药一次或两次。测量血液、肿瘤、肝脏和肾脏中的药物浓度。在一项随机的I期临床试验中，28名早期HER2+乳腺癌的初治女性患者接受了拉帕替尼1000或1500毫克每日一次(Qd)或500毫克bid，然后评估拉帕替尼在血浆和肿瘤中的稳定水平。在小鼠中，拉帕替尼在肿瘤中的浓度是血液中的4倍，半衰期是血液的4倍。在12小时的给药间隔内，肿瘤浓度超过了抑制HER2磷酸化的体外IC90(~900 nM或500 ng/mL)。在患者中，与血浆谷水平相比，服用Qd和Bid剂量的肿瘤水平分别高出6倍和10倍。肿瘤和血浆浓度之间的关系是复杂的，表明有多个决定因素。她的受体磷酸化程度随着拉帕替尼肿瘤浓度的不同而不同，这表明她的同源和异源二聚体的变化。拉帕替尼的血浆浓度低估了肿瘤药物的水平，这表明最佳剂量应集中在作用部位，以避免不适当的剂量增加。需要进行更大规模的临床试验，以确定最佳剂量和时间表，以实现最大限度地抑制她的受体的肿瘤浓度。临床试验注册：NCT00359190
The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor. In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers. Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors. Clinical Trial Registration: NCT00359190