Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults
Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults
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DOI：
10.1111/bcp.12787
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发表时间：
2016-02-01
影响因子：
3.4
通讯作者：
de Jong, Jan
中科院分区：
文献类型：
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作者：
de Vries, Ronald;Smit, Johan W.;de Jong, Jan
艾美替尼是一种布鲁顿酪氨酸激酶抑制剂，用于治疗套细胞淋巴瘤或慢性淋巴细胞白血病。伊布替尼在首过和清除水平均经历细胞色素P450 3A介导的广泛快速氧化代谢，这可能导致口服生物利用度较低。本研究旨在研究禁食和进食状态下伊克替尼的绝对生物利用度（F），并评估葡萄柚汁（GFJ）对伊克替尼全身暴露的影响，以确定进食状态下逃离肠道的分数（F-g）和逃离肝脏提取的分数（F-h）。B（560 mg PO依替尼，进食，饮用葡萄糖饮料后给药）和C（140 mg口服依替尼，进食，给药前摄入GFJ）。单次静脉内（i. v.）结果治疗A、B和C的估计F'分别为3.9%、8.4%和15.9%。摄食状态下的F-g和F-h分别为47.0%和15.9%。不良事件的严重程度为轻度至中度（1-2级），并解决了没有后遗症结束的study.ConclusionThe的绝对口服生物利用度低，范围从3.9%，在空腹状态下的8.4%，当给药前30分钟的标准早餐没有GFJ和15.9%与GFJ。在空腹和餐后条件下，无论GFJ摄入状态如何，单次口服和静脉给药后，伊布替尼的耐受性良好。
AimsIbrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (F-g) and the fraction escaping hepatic extraction (F-h) in the fed state.MethodsAll participants received treatment A [560mg oral ibrutinib, under fasting conditions], B (560mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100g C-13(6)-ibrutinib was administered 2h after each oral dose.ResultsThe estimated F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. F-g and F-h in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study.ConclusionThe absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.