Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
F. Hoffmann-La Roche AG, Basel, Switzerland.
J Clin Pharmacol. 2022 Feb;62(2):232-244. doi: 10.1002/jcph.1968. Epub 2021 Nov 8.
Emicizumab is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII to prevent bleeds in patients with hemophilia A. The dose selection for the first-in-child phase III study of emicizumab was addressed by pediatric pharmacokinetic prediction using an adult/adolescent population pharmacokinetic model developed in phase I-I/II studies. The model was modified to incorporate functions describing the age-dependent increase in body weight (BW) with or without clearance maturation to account for the differences in emicizumab pharmacokinetics between adults/adolescents and children. A minimal dose anticipated to achieve in children the same target efficacious exposure as for adults/adolescents was identified when considering BW and clearance maturation. It was the same BW-based dose as for adults/adolescents and was selected for the starting dose for the pediatric study. Whether considering clearance maturation or not in addition to BW led to uncertainty in the pediatric pharmacokinetic prediction and dose selection, which informed implementation of a dose-adapting scheme in the study design. Exposure matching to adults/adolescents was ultimately achieved in children with the starting dose, indicating that consideration of clearance maturation in addition to BW provided adequate pediatric pharmacokinetic predictions for emicizumab. This pharmacokinetic finding in conjunction with exposure-response information served as a basis for the efficacy demonstrated in children, avoiding a time-consuming process for exploring an optimal pediatric dose of emicizumab. This experience indicates that a model-based framework helped optimize the pediatric dose selection and study design, thereby streamlining the development process with extrapolation, of emicizumab for children.
依库珠单抗是一种双特异性抗体，可模拟激活的凝血因子 VIII 的辅助因子功能，从而预防血友病 A 患者出血。依库珠单抗首次用于儿童的 III 期研究的剂量选择是通过使用在 I 期-I/II 期研究中开发的成人/青少年群体药代动力学模型进行儿科药代动力学预测来解决的。该模型经过修改，纳入了描述体重（BW）随年龄增长的功能，以及是否存在清除成熟，以解释依库珠单抗在成人/青少年和儿童之间的药代动力学差异。在考虑 BW 和清除成熟的情况下，确定了最小剂量，预计该剂量可使儿童达到与成人/青少年相同的目标有效暴露。这是与成人/青少年相同的基于 BW 的剂量，被选为儿科研究的起始剂量。是否考虑除 BW 以外的清除成熟会导致儿科药代动力学预测和剂量选择的不确定性，这为研究设计中的剂量调整方案的实施提供了信息。通过起始剂量，儿童实现了与成人/青少年的暴露匹配，表明除 BW 以外考虑清除成熟为依库珠单抗提供了足够的儿科药代动力学预测。该药代动力学发现与暴露-反应信息相结合，为儿童的疗效提供了依据，避免了探索依库珠单抗最佳儿科剂量的耗时过程。这一经验表明，基于模型的框架有助于优化儿科剂量选择和研究设计，从而简化了依库珠单抗在儿童中的扩展开发过程。
