Population Pharmacokinetics of the BTK Inhibitor Acalabrutinib and its Active Metabolite in Healthy Volunteers and Patients with B-Cell Malignancies
Population Pharmacokinetics of the BTK Inhibitor Acalabrutinib and its Active Metabolite in Healthy Volunteers and Patients with B-Cell Malignancies
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DOI：
10.1007/s40262-018-0725-7
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发表时间：
2019-05-01
影响因子：
4.5
通讯作者：
Al-Huniti, Nidal
中科院分区：
文献类型：
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作者：
Edlund, Helena;Lee, Sun Ku;Al-Huniti, Nidal
布鲁顿酪氨酸激酶（BTK）是b细胞受体信号传导的关键成分，对细胞增殖至关重要。Acalabrutinib是一种选择性共价BTK抑制剂，最近被加速批准用于治疗复发/难治性套细胞淋巴瘤。本分析表征了阿卡拉布替尼及其代谢物ACP-5862的群体药代动力学（PK）。方法从成人b细胞恶性肿瘤患者的6个I/II期临床试验和健康志愿者的7个I期临床试验中获得数据。使用非线性混合效应模型分析了15至400mg剂量水平下的混合浓度-时间数据。基本模型参数按体重进行缩放并归一化为70kg（固定指数：清除和体积分别为0.75和1）。采用全协变量方法评估剂量、健康组/疾病状况、肝肾损害、减酸剂的使用、种族和性别的相关影响。结果共获得阿卡鲁替尼11196份、ACP-5862浓度-时间样品1068份。两种分析物的PK都很好地描述了使用双室处置模型。阿卡拉布替尼吸收用顺序零阶和一阶常数和滞后时间表征。阿卡拉布替尼的表观清除率（CL/F）为169 L/h （95% CI 159-175）。与100mg剂量组相比，15mg和400mg剂量组CL/F分别升高1.44倍和降低0.77倍。ACP-5862的清除率为21.9 L/h （95% CI 19.5-24.0）。代谢分数固定为0.4。阿卡拉布替尼的中心和周围分布容积分别为33.1 L （95% CI 24.4-41.0）和226 L (95% CI 149-305)， ACP-5862的中心和周围分布容积分别为38.5L （95% CI 31.6-49.2）和38.4 L （95% CI 32.3-47.9）。所调查的协变量均未导致暴露量发生有临床意义的变化。结论阿卡鲁替尼及其代谢物ACP-5862的钾代动力学特性得到了充分表征。阿卡拉布替尼CL/F随剂量增加而下降，但在75 ~ 250mg范围内趋势不大。不需要对内在或外在协变量进行剂量调整。
IntroductionBruton tyrosine kinase (BTK) is a key component of B-cell receptor signalling, critical for cell proliferation. Acalabrutinib, a selective, covalent BTK inhibitor, recently received an accelerated approval in relapsed/refractory mantle cell lymphoma. This analysis characterized the population pharmacokinetics (PK) of acalabrutinib and its metabolite ACP-5862.MethodsData were obtained from six phase I/II trials in adult patients with B-cell malignancy and seven phase I trials in healthy volunteers. Pooled concentration-time data, at dose levels ranging from 15 to 400mg, were analysed using non-linear mixed-effects modelling. Base model parameters were scaled with body weight and normalized to 70kg (fixed exponents: 0.75 and 1 for clearance and volumes, respectively). A full covariate approach was used to evaluate any relevant effects of dose, health group/disease status, hepatic and renal impairment, use of acid-reducing agents, race and sex.ResultsA total of 11,196 acalabrutinib and 1068 ACP-5862 concentration-time samples were available. The PK of both analytes were well described using two-compartment disposition models. Acalabrutinib absorption was characterized using sequential zero- and first-order constants and a lag time. Apparent clearance (CL/F) of acalabrutinib was 169 L/h (95% CI 159-175). Relative to the 100mg dose group, the 15 and 400mg dose groups showed a 1.44-fold higher and 0.77-fold lower CL/F, respectively. The clearance for ACP-5862 was 21.9 L/h (95% CI 19.5-24.0). The fraction metabolized was fixed to 0.4. The central and peripheral volumes of distribution were 33.1 L (95% CI 24.4-41.0) and 226 L (95% CI 149-305) for acalabrutinib, and 38.5L (95% CI 31.6-49.2) and 38.4 L (95% CI 32.3-47.9) for ACP-5862. None of the investigated covariates led to clinically meaningful changes in exposure.ConclusionThe PK of acalabrutinib and its metabolite ACP-5862 were adequately characterized. Acalabrutinib CL/F decreased with increasing dose, but the trend was small over the 75-250mg range. No dose adjustment was necessary for intrinsic or extrinsic covariates.