Use of pharmacokinetic versus pharmacodynamic endpoints to support human dose predictions: implications for rational drug design and early clinical development

The predicted human dose regimen of new chemical entities represents the most holistic and clinically relevant measure of drug-likeness upon which to base decisions in drug design and selection of candidate molecules for further development. Likewise, the predicted human dose regimen for efficacy and safety provides critical insight into clinical development planning. As such, human dose predictions are commonly generated in early stages of research and continually revisited as new data are generated through development. In this work, the authors illustrate scenarios where conventional approaches based on discrete pharmacokinetic metrics are inappropriate and propose a generalizable approach leveraging a predicted average pharmacodynamic effect rather than pharmacokinetic metrics. Preclinical and clinical data of a JAK inhibitor, tofacitinib, were used to illustrate the relative value of this approach to human dose prediction. Due to the simplicity of implementation, pharmacokinetic-based approaches which target a discrete maximal, average, or minimum concentration have been widely used across the pharmaceutical industry. However, in emphasizing only one point on the overall exposure-time profile, such approaches can be misleading in terms of the expected pharmacodynamic effect. For future projections, the authors recommend using the average pharmacodynamic effect-based approach to calculate human efficacious dose.新化学实体的预测人体给药方案，是衡量类药性最具整体性与临床相关性的核心指标，可作为药物设计以及遴选候选分子开展后续开发的决策依据。同样，针对有效性与安全性的预测人体给药方案，可为临床开发计划提供关键洞察。有鉴于此，人体剂量预测通常在研究早期阶段生成，并会随着开发过程中产生的新数据不断被重新审视与迭代更新。本研究中，作者阐明了基于离散药代动力学（pharmacokinetic）指标的传统方法并不适用的场景，并提出了一种可推广的新方法：该方法依托预测得到的平均药效学（pharmacodynamic）效应，而非药代动力学指标。研究以JAK抑制剂托法替布（tofacitinib）的临床前与临床数据为例，展示了该方法在人体剂量预测中的相对价值。由于实现流程简便，以离散的最大、平均或最小浓度为目标的基于药代动力学的方法，已在全球制药行业得到广泛应用。然而，这类方法仅关注暴露-时间曲线中的单一节点，在预期药效学效应方面可能会产生误导。针对未来的剂量预测，作者建议采用基于平均药效学效应的方法来计算人体有效剂量。