对伴有前蛋白转化酶枯草溶菌素 9 功能获得性或载脂蛋白 B 功能丧失性突变的家族性高胆固醇血症患者进行阿利西尤单抗的药代动力学和药效学评估。

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.

机构信息

School of Medicine, University of Utah, Salt Lake City, UT, USA.

CHU de Nantes - Hôpital Nord Laennec, Saint-Herblain, France.

出版信息

J Clin Lipidol. 2019 Nov-Dec;13(6):970-978. doi: 10.1016/j.jacl.2019.10.007. Epub 2019 Oct 21.

DOI:10.1016/j.jacl.2019.10.007

PMID:31767518

Abstract

BACKGROUND

Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm).

OBJECTIVE

The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm.

METHODS

Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22.

RESULTS

At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group.

CONCLUSIONS

Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm.

CLINICAL TRIAL REGISTRATION

NCT01604824; clinicaltrials.gov.

摘要

背景

家族性高胆固醇血症的特征是低密度脂蛋白胆固醇（LDL-C）水平升高，家族性高胆固醇血症的病因包括载脂蛋白 B（APOB）功能丧失突变（LOFm）和前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）功能获得性突变（GOFm）。

目的

本研究旨在比较 APOB LOFm 与 PCSK9 GOFm 患者中 alirocumab 的药代动力学和药效学。

方法

接受最大耐受降脂治疗后 LDL-C≥70mg/dL 的 6 名 APOB LOFm 和 17 名 PCSK9 GOFm 携带者患者在第 0、2、4、6 周接受 alirocumab 150mg，第 8 周给予安慰剂，第 10 周给予 alirocumab，第 12、14 周给予安慰剂，然后在第 22 周进行随访。

结果

第 8 周时，APOB LOFm 携带者的平均±标准误差（SE）alirocumab 浓度高于 PCSK9 GOFm 携带者（12.12±1.81 vs 16.74±2.53mg/L）。与 PCSK9 GOFm 携带者相比，APOB LOFm 携带者在第 8 周时的总 PCSK9（6.56±0.73mg/L）和游离 PCSK9（0.025±0.016mg/L）的平均±SE 值更高（分别为 0.025±0.016mg/L）。尽管观察到 PCSK9 抑制作用更大，但 APOB LOFm 携带者的 LDL-C 平均减少百分比（55.3±1.0%）低于 PCSK9 GOFm 携带者（73.1±0.9%）。PCSK9 GOFm 组 16 名患者（94.1%）和 APOB LOFm 组 5 名患者（83.3%）出现治疗相关不良事件。