Pfizer Inc., South San Francisco and San Diego, CA, USA.
Mirati Therapeutics Inc., San Diego, CA, USA.
Cardiovasc Ther. 2018 Feb;36(1). doi: 10.1111/1755-5922.12309. Epub 2017 Nov 23.
Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.
The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL).
Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related.
Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.
四项 I 期研究招募了原发性高胆固醇血症患者，旨在评估 bococizumab（一种前蛋白转化酶枯草溶菌素/克那霉 9（PCSK9）抑制剂）单次和多次给药的安全性、耐受性、药代动力学和药效学。
四项 I 期研究中，高胆固醇血症受试者的给药方案如下：（1）单次递增静脉内（IV） bococizumab（0.3、1、3、6、12 或 18mg/kg）或安慰剂（n=48；基线低密度脂蛋白胆固醇[LDL-C]≥130mg/dL）；（2）在阿托伐他汀 40mg/天的基础上加用单次 IV bococizumab（0.5 或 4mg/kg；无安慰剂）（n=24）；（3）单次固定皮下（SC） bococizumab（100 或 200mg）或 IV bococizumab（200mg；无安慰剂；n=49；基线 LDL-C≥130mg/dL）；（4）每周 IV bococizumab（0.25、0.5、1 或 1.5mg/kg）或安慰剂 4 周（n=67；基线 LDL-C≥130mg/dL）。
单次 IV 或 SC 剂量及多次 IV 剂量后，bococizumab 的药代动力学特征良好。单次给药 bococizumab 的暴露量呈剂量依赖性增加，清除率随剂量增加而降低。在单次给药研究中，与安慰剂组相比，接受 bococizumab 治疗的受试者的 LDL-C 基线平均最大百分比降幅范围为 43%（0.3mg/kg）至 84%（18mg/kg）；在多次给药研究中，接受 bococizumab 治疗的受试者的 LDL-C 最大降幅范围为 55%（0.25mg/kg）至 66%（1mg/kg），而安慰剂组的降幅为 9%。在所有研究中，不良事件均不常见、短暂且与剂量无关。
bococizumab 通常安全且耐受良好。四项研究中，bococizumab 均显著降低 LDL-C 水平。
