Use of a physiologically based pharmacokinetic-pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial
Use of a physiologically based pharmacokinetic-pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial
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DOI：
10.1111/bcp.14528
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发表时间：
2020-09-06
影响因子：
3.4
通讯作者：
Sciberras, David
中科院分区：
文献类型：
--
作者：
Johnson, Trevor N.;Abduljalil, Khaled;Sciberras, David
目的 建立并验证雷普地尔成人生理药代动力学 (PBPK) 模型，并将其与源自体外数据的药效 (PD) 受体占据 (RO) 模型联系起来。使该模型适应儿科人群，并根据 RO 预测婴儿的起始剂量和递增剂量。使用该模型指导 2 至 14 个月大婴儿痉挛症儿童的临床试验中的个体化用药。方法建立雷拉地尔的PBPK模型来研究禁食和进食成人口服给药后药物的全身暴露；然后通过 PD 模型将其链接到 RO。然后将该模型扩展到包括发育生理学和个体发育，以预测婴儿剂量的递增，这将导致基于每日两次 (b.i.d.) 给药方案后的平均未结合浓度的特定 RO 为 20%、40% 和 60%。临床试验中的剂量进展是基于针对 PBPK 预测观察到的浓度-时间数据。结果 对于儿科预测，根据实验证据，雷拉地尔的消除没有个体发育。预测出价剂量范围为 20% RO 的 0.04 mg/kg、40% RO 的 0.1 mg/kg 至 60% RO 的 0.21 mg/kg。对于研究中招募的所有婴儿，观察到的 0.04 mg/kg 和后续剂量后的浓度-时间数据均在 PBPK 模型预测的 5(th) 和 95(th) 百分位数内。结论 据我们所知，这是首次使用与 RO 相关的 PBPK 模型来指导儿科临床试验实时阶段的剂量选择和剂量升级。
Aims To build and verify a physiologically based pharmacokinetic (PBPK) model for radiprodil in adults and link this to a pharmacodynamic (PD) receptor occupancy (RO) model derived fromin vitrodata. Adapt this model to the paediatric population and predict starting and escalating doses in infants based on RO. Use the model to guide individualized dosing in a clinical trial in 2- to 14-month-old children with infantile spasms. Methods A PBPK model for radiprodil was developed to investigate the systemic exposure of the drug after oral administration in fasted and fed adults; this was then linked to RO via a PD model. The model was then expanded to include developmental physiology and ontogeny to predict escalating doses in infants that would result in a specific RO of 20, 40 and 60% based on average unbound concentration following a twice daily (b.i.d.) dosing regimen. Dose progression in the clinical trial was based on observed concentration-time data against PBPK predictions. Results For paediatric predictions, the elimination of radiprodil, based on experimental evidence, had no ontogeny. Predicted b.i.d. doses ranged from 0.04 mg/kg for 20% RO, 0.1 mg/kg for 40% RO to 0.21 mg/kg for 60% RO. For all infants recruited in the study, observed concentration-time data following the 0.04 mg/kg and subsequent doses were within the PBPK model predicted 5(th)and 95(th)percentiles. Conclusion To our knowledge, this is the first time a PBPK model linked to RO has been used to guide dose selection and escalation in the live phase of a paediatric clinical trial.