Planchard David, Brown Kathryn H, Kim Dong-Wan, Kim Sang-We, Ohe Yuichiro, Felip Enriqueta, Leese Philip, Cantarini Mireille, Vishwanathan Karthick, Jänne Pasi A, Ranson Malcolm, Dickinson Paul A
Department of Medical Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805, Villejuif, France.
Quantitative Clinical Pharmacology, AstraZeneca, Macclesfield, UK.
Cancer Chemother Pharmacol. 2016 Apr;77(4):767-76. doi: 10.1007/s00280-016-2992-z. Epub 2016 Feb 22.
Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.
AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state.
Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure.
Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.
奥希替尼（AZD9291）每日一次80毫克已获美国食品药品监督管理局批准，用于治疗转移性表皮生长因子受体（EGFR）T790M阳性非小细胞肺癌（NSCLC）患者，这些患者的疾病先前在EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗中出现进展。对奥希替尼的药代动力学（PK）进行评估，以确定剂量和给药间隔、是否可在全球采用固定剂量给药方法以及制剂和食物对药物暴露的影响。
AURA研究（NCT01802632）：在晚期NSCLC患者中测定奥希替尼（每日20 - 240毫克）的单剂量和多剂量PK。生物利用度研究（NCT01951599）：在健康志愿者中，分别测定空腹服用胶囊、溶液或片剂剂型以及进食和空腹状态下服用片剂剂型的奥希替尼（20毫克）单剂量PK。
奥希替尼吸收缓慢，20至240毫克剂量下暴露量呈剂量比例增加。分布广泛，清除率低至中等，平均半衰期为48.3小时。给药15天达到稳态，与单剂量PK一致，峰谷比为1.6。两种活性代谢物的循环水平约为奥希替尼暴露量的10%。种族似乎不影响暴露量。健康志愿者中的奥希替尼PK曲线与患者相似，且不受制剂影响。食物导致暴露量出现临床上无显著意义的增加。
奥希替尼的PK支持每日一次给药；亚洲和非亚洲人群使用相同剂量；采用固定剂量给药方法；食物对暴露量影响极小；可改用片剂剂型而无需改变剂量或给药方案。在整个给药期间，奥希替尼血浆浓度持续维持，这被认为对疗效最为理想。
