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Use of a physiologically based pharmacokinetic-pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial

机译:在儿科临床试验期间使用生理基础的药代动力学药物动力学模型进行初始剂量预测和升级

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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.
机译:目的建立并验证拉地普地尔在成人中的生理药代动力学(PBPK)模型,并将其与源自vitrodata的药效学(PD)受体占用(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个月大婴儿痉挛患儿的临床试验中的个体化给药。方法建立拉地普地尔的PBPK模型,研究禁食和喂食成人口服拉地普地尔后的全身暴露情况;然后通过PD模型将其连接到RO。然后,该模型被扩展到包括发育生理学和个体发育,以预测婴儿剂量的增加,从而根据每日两次(b.i.d.)给药方案后的平均未结合浓度,产生20%、40%和60%的特定RO。临床试验中的剂量进展基于观察到的浓度-时间数据和PBPK预测。结果对于儿科预测,基于实验证据,消除拉地普地尔没有个体发生。预计的b.i.d.剂量范围为20%反渗透0.04 mg/kg、40%反渗透0.1 mg/kg至60%反渗透0.21 mg/kg。对于本研究中招募的所有婴儿,在0.04 mg/kg和后续剂量后观察到的浓度-时间数据均在PBPK模型预测的第5百分位和第95百分位范围内。结论据我们所知,这是第一次使用与RO相关的PBPK模型来指导儿科临床试验现场阶段的剂量选择和升级。

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