Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease
Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer's disease
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DOI：
10.1186/s13195-020-0580-2
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发表时间：
2020-01-22
影响因子：
9
通讯作者：
Quartino, Angelica
中科院分区：
文献类型：
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作者：
Yoshida, Kenta;Moein, Anita;Quartino, Angelica
Crenezumab是一种完全人源化的抗β-淀粉样蛋白（A β）免疫球蛋白G4（IgG 4）单克隆抗体，可结合单体和聚集形式的A β。我们评估了克瑞珠单抗的药代动力学（PK）/药效学（PD）及其与来自II期ABBY和BLAZE研究以及Ib期GN 29632研究的血清/血浆和脑脊液（CSF）样本中单体A β（1-40）和A β（1-42）肽的相互作用。方法在ABBY、BLAZE和GN 29632研究中，轻度至中度AD患者接受安慰剂或克瑞珠单抗（300 mg皮下注射，每2周[q2 w]，或15 mg/kg、30 mg/kg、45 mg/kg、60 mg/kg或120 mg/kg静脉注射，q4 w）治疗。血清/血浆PK/PD分析包括来自所有三项研究中接受crenezumab的131名患者的样本。CSF PK/PD分析包括来自在ABBY或BLAZE中接受克瑞珠单抗的76名患者的样本。还评价了基线患者因素对A β谱的影响。结果在15至120 mg/kg q4 w之间，克雷内珠单抗的血清浓度以剂量成比例的方式增加。克瑞珠单抗给药后，总单体血浆A β（1-40）和A β（1-42）水平显著升高。平均crenezumab CSF/血清比值与0.3%相似，并且在给药队列/给药途径之间相似。在第69周时，未观察到克瑞珠单抗浓度与CSF中A β（1-42）增加之间存在明显相关性。靶向介导的药物分布（TMDD）模型很好地描述了观察到的克瑞珠单抗和A β的血浆浓度-时间曲线。克瑞珠单抗的消除清除率（CLel）和中心分布容积（V-cent）估计分别为0.159 L/天和2.89 L，对应于类似于20天的半衰期。皮下生物利用度估计为66.2%。结论Crenezumab PK与剂量成比例，高达120 mg/kg，半衰期与IgG单克隆抗体一致。我们的研究结果为轻中度AD患者的外周靶点参与提供了证据。该研究还表明，基于模型的方法可用于推断PK/PD与未测量物质（如游离血浆A β水平）的关系。
Background Crenezumab, a fully humanized anti-beta-amyloid (A beta) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of A beta. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) of crenezumab and its interaction with monomeric A beta(1-40) and A beta(1-42) peptides in serum/plasma and cerebrospinal fluid (CSF) samples from the phase II ABBY and BLAZE studies and the phase Ib GN29632 study. Methods In ABBY, BLAZE, and GN29632 studies, patients with mild-to-moderate AD were treated with either placebo or crenezumab (300 mg subcutaneously every 2 weeks [q2w], or 15 mg/kg, 30 mg/kg, 45 mg/kg, 60 mg/kg, or 120 mg/kg intravenously q4w). Serum/plasma PK/PD analyses included samples from 131 patients who received crenezumab in all three studies. CSF PK/PD analyses included samples from 76 patients who received crenezumab in ABBY or BLAZE. The impact of baseline patient factors on A beta profiles was also evaluated. Results The serum concentration of crenezumab increased in a dose-proportional manner between 15 and 120 mg/kg q4w. Total monomeric plasma A beta(1-40) and A beta(1-42) levels significantly increased after crenezumab administration. The mean crenezumab CSF to serum ratio was similar to 0.3% and was similar across dosing cohorts/routes of administration. No clear correlation was observed between crenezumab concentration and A beta(1-42) increase in CSF at week 69. The target-mediated drug disposition (TMDD) model described the observed plasma concentration-time profiles of crenezumab and A beta well. Elimination clearance (CLel) and central volume of distribution (V-cent) of crenezumab were estimated at 0.159 L/day and 2.89 L, respectively, corresponding to a half-life of similar to 20 days. Subcutaneous bioavailability was estimated at 66.2%. Conclusions Crenezumab PK was dose proportional up to 120 mg/kg, with a half-life consistent with IgG monoclonal antibodies. Our findings provide evidence for peripheral target engagement in patients with mild-to-moderate AD. The study also showed that a model-based approach is useful in making inference on PK/PD relationship with unmeasured species such as free plasma A beta levels.