Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500
Target-Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model-Informed Dose Selection for the First-in-Human Study of AVB-S6-500
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DOI：
10.1111/cts.12706
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发表时间：
2019-10-25
影响因子：
3.9
通讯作者：
McIntyre, Gail
中科院分区：
文献类型：
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作者：
Bonifacio, Laura;Dodds, Michael;McIntyre, Gail
AVB-S6-500在临床前癌症模型中中和生长停滞特异性6（GAS 6）蛋白，并有效抑制AXL信号传导。基于临床预测的靶点（GAS 6）抑制，使用靶点介导的药物分布（TMDD）药代动力学/药效学（PK/PD）模型选择AVB-S6-500的首次人体（FIH）剂量。将TMDD对AVB-S6 -500清除率的影响纳入标准二室模型，提供平行的线性和非线性清除率。食蟹猴中观察到的AVB-S6 -500和GAS 6浓度数据以及相关种属间差异用于预测人体中的PK（血清浓度）/PD（GAS 6抑制）关系。模拟拟定FIH剂量1、2.5、5和10 mg/kg的人体暴露和GAS 6抑制。在最初的健康志愿者研究中，选择1 mg/kg的剂量以靶向GAS 6抑制2周。预期最高拟定FIH剂量的食蟹猴：人比率产生超过非临床未观察到不良事件水平的10倍边界，同时维持> 90% GAS 6抑制。在人类受试者中，首次给药（1 mg/kg）模型预测和临床观察到的最大浓度（C-max）在预测值的10%范围内; 5 mg/kg重复给药在预测值的1%（C-max）和45%（从时间0至给药间隔结束的血清浓度-时间曲线下面积）范围内。对于1 mg/kg剂量，预测的GAS 6抑制持续时间为14天是准确的。PK/PD模型加速了AVB-S6 -500的临床开发，最大限度地减少了癌症患者对亚治疗剂量的暴露，并合理指导了患者的最佳剂量。
AVB-S6-500 neutralized growth arrest-specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target-mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first-in-human (FIH) doses for AVB-S6-500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB-S6-500 clearance was incorporated into a standard two-compartment model, providing parallel linear and nonlinear clearance. Observed AVB-S6-500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10-fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model-projected and clinically observed maximal concentration (C-max) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (C-max) and 45% (area under the serum concentration-time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB-S6-500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.