Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden.
J Pharmacokinet Pharmacodyn. 2018 Aug;45(4):637-647. doi: 10.1007/s10928-018-9594-9. Epub 2018 Jun 8.
Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering the binding of OMA to free IgE and the subsequent formation of an OMA-IgE complex. The performance of the reduced and optimized designs was evaluated with respect to: efficiency, parameter uncertainty and predictions of free target. It was possible to reduce the number of samples in the study by 30% while still maintaining an efficiency of almost 90%. A reduction in sampling duration by two-thirds resulted in an efficiency of 75%. Omission of any analyte measurement or a reduction of the number of dose levels was detrimental to the efficiency of the designs (efficiency ≤ 51%). However, other metrics were, in some cases, relatively unaffected, showing that multiple metrics may be needed to obtain balanced assessments of design performance.
针对可溶性靶点的单克隆抗体通常较为丰富，包括在较长时间内对多个分析物进行采样。基于此类研究中获得的数据构建的预测模型在所有药物开发阶段都可能有用。如果可以通过减少设计（例如减少样本量或缩短持续时间）来维持足够的模型预测，那么可能会提倡使用这种设计。以奥马珠单抗（OMA）为例，评估了基于已发表研究减少和优化丰富设计的效果。通过考虑 OMA 与游离 IgE 的结合以及随后形成的 OMA-IgE 复合物，使用基于靶标的药物处置模型来描述 OMA 的药代动力学。根据以下方面评估简化和优化设计的性能：效率、参数不确定性和对游离靶标的预测。通过将研究中的样本数量减少 30%，仍然可以保持近 90%的效率。采样持续时间减少三分之二可使效率达到 75%。省略任何分析物测量或减少剂量水平对设计效率都不利（效率≤51%）。但是，在某些情况下，其他指标相对不受影响，这表明可能需要多种指标来获得对设计性能的平衡评估。
