Vishwanathan Karthick, Cantarini Mireille, So Karen, Masson Eric, Fetterolf Jennifer, Ramalingam Suresh S, Harvey R Donald
Clinical Pharmacology and Safety Sciences, Research & Development, AstraZeneca, Waltham, Massachusetts, USA.
Oncology Research & Development, AstraZeneca, Macclesfield, UK.
Clin Transl Sci. 2020 Jan;13(1):41-46. doi: 10.1111/cts.12688. Epub 2019 Sep 24.
A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (C )) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.
一项I期开放标签研究（NCT02197234）评估了奥希替尼对晚期表皮生长因子受体（EGFR）突变的非小细胞肺癌患者以及EGFR酪氨酸激酶抑制剂治疗后疾病进展患者辛伐他汀暴露量的影响。在此，我们报告了对两名患者（患者1和患者2）的回顾性分析，这两名患者在接受奥希替尼治疗前有肝转移且辛伐他汀暴露量高，治疗后发生了变化。患者在第1天（D1）和第31天口服单剂量40 mg辛伐他汀，在第3 - 32天每天口服一次80 mg奥希替尼。基线时，两名患者的肝功能检查均异常（Child-Pugh评分分别为6分和8分），有显著肝转移，且在单次服用辛伐他汀后，其暴露量比所有其他患者高（约10倍）。连续31天奥希替尼治疗后，辛伐他汀的暴露量（血浆浓度-时间曲线从零到无穷大的面积（AUC）和最大血浆浓度（C））以及肝功能检查指标，如丙氨酸转氨酶、天冬氨酸转氨酶和胆红素恢复至人群平均值。此外，在计算机断层扫描中，患者1和患者2的肝转移分别减少了约50%和约80%。第1天辛伐他汀暴露量高可能是由于肝转移导致肝脏首过代谢受损。奥希替尼治疗使肝脏疾病负担减轻，可能导致肝功能恢复到正常水平。
