拉帕替尼是HER1和HER2双受体酪氨酸激酶小分子口服抑制剂，先后于2007年和2013年被美国和中国内陆批准用于联合卡培他滨治疗HER2阳性晚期乳腺癌。由于拉帕替尼与食物同时服用后血药浓度增加，例如与低脂饮食或高脂饮食同时服用，血药浓度曲线下面积分别增加大约3或4倍、血药浓度峰值分别升高大约2.5或3倍，故产品说明书建议应在餐前至少1小时或餐后至少1小时服用，并且建议将每日剂量一次服用，不推荐分次服用；不过，产品说明书同时建议卡培他滨与食物同时服用，或餐后30分钟内服用，而且每天分两次口服，间隔约12小时。如此复杂的用法令人匪夷所思：一是造成拉帕替尼的浪费，二是增加拉帕替尼的恶心呕吐腹泻等胃肠刺激反应，三是不便患者每天同时服用两种药物。2007年，美国临床肿瘤学会《临床肿瘤学杂志》曾经发表芝加哥大学肿瘤内科学家的建议：将拉帕替尼由每天1次空腹服用5片，改为每天分2次随餐服用各1片，能够节省至少60%的药量，血药浓度相似，胃肠刺激反应减少，每月可以节省至少1740美元的药费。可惜，该建议始终未被傲慢的FDA和制药厂商采纳。这家制药厂商倒是非常乐意花费将近十亿美金搞了一个伟大而又极其复杂的早期乳腺癌辅助治疗临床研究，结果以失败而告终……
2020年2月14日，美国转化肿瘤学会《肿瘤学家》在线发表中山大学附属肿瘤医院徐菲、李家平、夏雯、廖海、陆倩仪、张靖敏、袁慧敏、张凯、郑秋帆、秦歌、翟清莲、洪若熙、王树森等学者的小型研究报告，对中国晚期乳腺癌患者空腹或随餐服用拉帕替尼的有效性和安全性进行了初步比较。
SYSU002: To Discuss the Best Mode for Taking Lapatinib Under the Influence of the Diet (NCT03075995)
该单中心非盲前瞻自身对照二期临床研究于2017年6月～2018年4月从中山大学附属肿瘤医院入组中国晚期乳腺癌患者10例，给予拉帕替尼＋化疗。首先连续10天空腹服用拉帕替尼，随后连续10天随餐服用拉帕替尼。每10天的第9天和第10天，通过液相色谱法测定血药浓度，绘制血药浓度（纵坐标）时间（横坐标）曲线，计算变异系数（标准差与平均数比值的百分数，代表样本的分散程度）。
结果，拉帕替尼平均血药浓度：
空腹服药：0.88±0.39mg/L（变异系数：45%）
随餐服药：2.53±0.77mg/L（变异系数：30%）
血药浓度时间曲线下面积：
空腹服药：21.23± 8.91mg*h/L（变异系数：42%）
随餐服药：60.60±16.64mg*h/L（变异系数：27%）
随餐服药与空腹服药相比，拉帕替尼的血药浓度显著较高（威尔科克森配对检验，P=0.005）。
此外，研究期间未见严重不良事件，随餐服药与空腹服药相比，拉帕替尼相关不良事件相似。
因此，该小样本初步研究结果表明，对于中国晚期乳腺癌患者，随餐服药与空腹服药相比，可以显著提高拉帕替尼的血药浓度，药物相关毒性未见显著增加，故建议开展大样本临床研究，以充分了解拉帕替尼随餐给药的疗效，及其药物经济学意义。
这是目前为止首个探讨中国晚期乳腺癌患者随餐服用拉帕替尼效果的临床研究，虽然规模不大，但是意义不小。随着抗HER2靶向抑制剂的不断推陈出新，如今的拉帕替尼已是明日黄花蝶也愁，不过对于广大无力承担曲妥珠单抗、帕妥珠单抗、恩美曲妥珠单抗（T-DM1）等昂贵药物的中国晚期乳腺癌患者，仍然值得探讨如何优化拉帕替尼等小分子口服靶向抑制剂的用量用法。制药厂商也应反思，除了新产品大研究，还应搞一些老产品小研究，以减轻金字塔顶端下方芸芸众生的用药负担。
相关链接
Oncologist. 2020 Feb 14. [Epub ahead of print]
Administration of Lapatinib with Food Increases Its Plasma Concentration in Chinese Patients with Metastatic Breast Cancer: A Prospective Phase II Study.
Xu F, Lee K, Xia W, Liao H, Lu Q, Zhang J, Yuan H, Zhang K, Zheng Q, Qin G, Zhai Q, Hong R, Jiang K, Li Y, Wang S.
Sun Yat-sen University Cancer Center, Guangzhou, China.
LESSONS LEARNED
Administration of lapatinib with food significantly increased its plasma concentration in Chinese patients with metastatic breast cancer.
There were no serious adverse events during the study and no significant differences in lapatinib-related adverse events between the fasted and fed states.
BACKGROUND: Lapatinib, a small molecular reversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2), was approved for use in combination with capecitabine to treat metastatic HER2-positive breast cancer. Administration of lapatinib in the fasted state was recommended; however, our preliminary phase II trial data showed that administration of lapatinib with food increased its concentration.
METHODS: This study was a single-center, open-label, and prospective self-controlled clinical study. Ten Chinese patients with metastatic breast cancer were enrolled from June 2017 to April 2018. They were required to receive lapatinib plus physician's choice of chemotherapy. Patients were required to take lapatinib orally on an empty stomach continually for 10 days, and then take lapatinib with food continually for the next 10 days. Plasma concentration was measured by liquid chromatography on the 9th and 10th day of each state.
RESULTS: Area under the concentration-time curve (AUC) of the fasted state and the fed state was 21.23 ± 8.91 mg*h/L (Coefficient of variation (CV)% 42%) and 60.60 ± 16.64 mg*h/L (CV% 27%), respectively. The mean plasma concentration in the fasted state was 0.88 ± 0.39 mg/L (CV% 45%), and that in the fed state was 2.53 ± 0.77 mg/L (CV% 30%). Compared with taking lapatinib on an empty stomach, receiving lapatinib with food significantly increased the plasma concentration of lapatinib (Wilcoxon match-paired test, p = .005). In addition, there were no serious adverse events during the study or significant difference in lapatinib-related adverse events between the two states.
CONCLUSIONS: Our study shows that receiving lapatinib with food can increase its plasma concentration with no significantly increased drug-related toxicity. We suggest that a larger-sample-size clinical trial is needed to fully understand the effect of administration of lapatinib with food.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03075995
DOI: 10.1634/theoncologist.2020-0044
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