吉特替尼的药代动力学特征：一种新型的 FLT-3 酪氨酸激酶抑制剂。
Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor.
机构信息
Astellas Pharma US, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA.
University of California San Francisco, San Francisco, CA, USA.
出版信息
Clin Pharmacokinet. 2020 Oct;59(10):1273-1290. doi: 10.1007/s40262-020-00888-w.
BACKGROUND AND OBJECTIVE
Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib.
METHODS
The pharmacokinetic profile of gilteritinib was assessed from five clinical studies.
RESULTS
Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20-450 mg). Median maximum concentration was reached 2-6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function.
CONCLUSIONS
Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.
CLINICAL TRIAL REGISTRATION
NCT02014558, NCT02456883, NCT02571816.
背景与目的
吉特替尼是一种新型、高度选择性的酪氨酸激酶抑制剂，已在美国、加拿大、欧洲、巴西、韩国和日本获得批准，用于治疗 FLT3 突变阳性的急性髓系白血病。本文描述了吉特替尼的临床药代动力学特征。
方法
从五项临床研究中评估了吉特替尼的药代动力学特征。
结果
吉特替尼每日一次给药呈剂量比例药代动力学特征（剂量范围 20-450mg）。单次和重复给药后，吉特替尼的中位最大浓度在 2-6 小时达到；平均消除半衰期为 113 小时。消除主要通过粪便。空腹和进食条件下，吉特替尼的暴露情况相当。吉特替尼主要通过细胞色素 P450（CYP）3A4 代谢；吉特替尼与伊曲康唑（一种强 P-糖蛋白抑制剂和 CYP3A4 抑制剂）或利福平（一种强 P-糖蛋白诱导剂和 CYP3A 诱导剂）联合用药显著影响了吉特替尼的药代动力学特征。吉特替尼与咪达唑仑（CYP3A4 底物）或头孢氨苄（多药和毒素外排 1 底物）联合用药时，未观察到有临床意义的相互作用。肝损伤受试者与肝功能正常受试者的游离吉特替尼暴露量相似。
结论
在健康受试者和复发性/难治性急性髓系白血病患者中，吉特替尼呈现出剂量比例药代动力学特征。吉特替尼的暴露量不受食物的显著影响。中至强 CYP3A 抑制剂对吉特替尼的暴露量有显著影响。吉特替尼与 CYP3A4 或多药和毒素外排 1 底物联合用药不影响底物浓度。肝损伤受试者与肝功能正常受试者的游离吉特替尼相似；肝损伤患者无需调整剂量。
临床试验注册
NCT02014558，NCT02456883，NCT02571816。
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