Department of Pharmacy, Franciscus Gasthuis, Rotterdam, The Netherlands.
Department of Internal Medicine, Franciscus Gasthuis, Rotterdam, The Netherlands.
Clin Pharmacokinet. 2018 Jan;57(1):21-29. doi: 10.1007/s40262-017-0565-x.
Histone deacetylase (HDAC) inhibitors cause an increase in acetylation that leads to an increase in DNA transcription and accumulation of different proteins, reducing cell proliferation and inducing cell death. Panobinostat is a first-in-line HDAC inhibitor approved for treating multiple myeloma in combination with bortezomib and dexamethasone. It is a pan-deacetylase inhibitor and therefore inhibits not only HDAC but also other deacetylases. The main mechanism of action of panobinostat is to inhibit HDAC, which causes cell cycle arrest and apoptosis, leading to it being an antineoplastic drug. Pooled data of multiple-dose studies show that an oral dose of panobinostat 20 mg resulted in a maximum plasma concentration (C ) of 21.6 ng/mL approximately 1 h after administration, while doses between 10 and 30 mg resulted in dose proportional plasma levels. The absolute bioavailability of panobinostat is 21.4%, and it is moderately bound to plasma proteins. Renal impairment does not influence the intrinsic pharmacokinetics of panobinostat, however hepatic impairment causes an increase in the plasma concentrations of this drug. Therefore, starting treatment at lower doses could be considered in patients with mild to moderate hepatic impairment. Different ethnic backgrounds have an influence on the pharmacokinetics of panobinostat; however, due to major interindividual variability, no dose adjustment is recommended. The area under the concentration-time curve of panobinostat changes significantly under cytochrome P450 (CYP) 3A4 inhibitors, CYP3A4 and CYP2D6 inducers, and P-glycoprotein inhibitors. Panobinostat itself is a CYP2D6 inhibitor, which influences the plasma levels of the CYP2D6 substrate dexamethasone. The main side effects of panobinostat are diarrhea, peripheral neuropathy, asthenia and fatigue; hematologic side effects include neutropenia, thrombocytopenia, and lymphocytopenia.
组蛋白去乙酰化酶（HDAC）抑制剂可引起乙酰化增加，从而导致 DNA 转录增加和不同蛋白质的积累，减少细胞增殖并诱导细胞死亡。帕比司他是一种一线 HDAC 抑制剂，与硼替佐米和地塞米松联合用于治疗多发性骨髓瘤。它是一种泛去乙酰化酶抑制剂，因此不仅抑制 HDAC，还抑制其他去乙酰化酶。帕比司他的主要作用机制是抑制 HDAC，导致细胞周期停滞和细胞凋亡，使其成为一种抗肿瘤药物。多项剂量研究的汇总数据显示，口服帕比司他 20mg 后约 1 小时达到最大血浆浓度（C ）为 21.6ng/mL，而 10 至 30mg 剂量则导致剂量比例的血浆水平。帕比司他的绝对生物利用度为 21.4%，并与血浆蛋白中度结合。肾功能不全不影响帕比司他的内在药代动力学，但肝损伤会导致该药物的血浆浓度增加。因此，对于轻度至中度肝损伤的患者，可以考虑较低剂量开始治疗。不同的种族背景对帕比司他的药代动力学有影响；然而，由于个体间的巨大变异性，不建议进行剂量调整。帕比司他的浓度-时间曲线下面积在细胞色素 P450（CYP）3A4 抑制剂、CYP3A4 和 CYP2D6 诱导剂和 P-糖蛋白抑制剂下显著改变。帕比司他本身是 CYP2D6 抑制剂，会影响 CYP2D6 底物地塞米松的血浆水平。帕比司他的主要副作用是腹泻、周围神经病、乏力和疲劳；血液学副作用包括中性粒细胞减少、血小板减少和淋巴细胞减少。
