Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.
Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.
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DOI：
10.1007/s00228-015-1967-z
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发表时间：
2016-02
影响因子：
2.9
通讯作者：
Suzuki K
中科院分区：
文献类型：
--
作者：
Mu S;Kuroda Y;Shibayama H;Hino M;Tajima T;Corrado C;Lin R;Waldron E;Binlich F;Suzuki K
Panobinostat是一种有效的泛去乙酰化酶抑制剂，在一项3期临床试验PANORAMA-1中，Panobinostat与硼替佐米和地塞米松联合治疗复发和难治性多发性骨髓瘤患者的无进展生存期（PFS）得到改善。本研究旨在在B2207一期临床试验中探讨panobinostat联合用药的暴露-反应关系，并与以往单药研究的数据进行对比。从PANORAMA-1 （n = 12）和B2207 （n = 12）试验中获得患者的Panobinostat血浆浓度-时间曲线。在B2207试验中，研究了panobinostat暴露的总缓解率（ORR）和主要不良事件（AE）。联合试验的Panobinostat PK数据与单药研究的数据进行了对比。在最大耐受剂量（MTD）下，0 ~ 24 h panobinostat曲线下面积几何平均值（auc0 ~ 24）为47.5 ng h/mL (77% CV)，最大血药浓度（Cmax）为8.1 ng/mL （90% CV）。这些值与PANORAMA-1中获得的暴露数据相当，但比未使用地塞米松的试验低20%，比单药试验低约50%，可能是由于地塞米松的酶诱导。panobinostat暴露水平越高，反应率越高，腹泻和血小板减少的发生率也越高。当与硼替佐米和地塞米松联合治疗复发和难治性多发性骨髓瘤患者时，观察到明显的panobinostat暴露- ae和暴露- orr关系。添加地塞米松促进最佳反应，即使血浆暴露的帕比司他减少。在未来的试验中应避免与强酶诱导剂联合使用，以防止进一步减少panobinostat的暴露。
Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure–response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies. Panobinostat plasma concentration–time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies. At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia. Apparent panobinostat exposure–AE and exposure–ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.