Danhof Meindert
Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
J Pharmacokinet Pharmacodyn. 2015 Oct;42(5):447-62. doi: 10.1007/s10928-015-9437-x. Epub 2015 Aug 30.
Gerhard Levy started his investigations on the "Kinetics of Drug Action in Disease States" in the fall of 1980. The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984-1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the relations between pharmacokinetics and pharmacodynamics. Together with the concepts in Levy's earlier publications "Kinetics of Pharmacologic Effects" (Clin Pharmacol Ther 7(3): 362-372, 1966) and "Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin" (Clin Pharmacol Ther 10(1): 22-35, 1969), they form a significant impulse to the development of physiology-based pharmacodynamic (PBPD) modeling as novel discipline in the pharmaceutical sciences. This paper reviews Levy's research on the "Kinetics of Drug Action in Disease States". Next it addresses the significance of his research for the evolution of PBPD modeling as a scientific discipline. PBPD models contain specific expressions to characterize in a strictly quantitative manner processes on the causal path between exposure (in terms of concentration at the target site) and the drug effect (in terms of the change in biological function). Pertinent processes on the causal path are: (1) target site distribution, (2) target binding and activation and (3) transduction and homeostatic feedback.
格哈德·利维于1980年秋开始了他关于“疾病状态下药物作用动力学”的研究。他的研究目标是研究药效学的个体间差异。为此，引入了理论概念和实验方法，这些方法能够评估药效学本身的变化，同时排除或考虑药代动力学伴随变化的混杂效应。这些概念被应用于多项研究中。1984年至1994年间发表在45篇论文中的研究结果显示，药效学存在相当大的差异。这些关于疾病状态下药物作用动力学的初步研究引发了关于药代动力学与药效学之间关系的进一步实验研究。与利维早期出版物《药理效应动力学》（《临床药理学与治疗学》7(3): 362 - 372, 1966）和《人体药理效应动力学：华法林的抗凝作用》（《临床药理学与治疗学》10(1): 22 - 35, 1969）中的概念一起，它们为基于生理学的药效学（PBPD）建模作为药物科学中的一门新学科的发展提供了重要推动力。本文回顾了利维关于“疾病状态下药物作用动力学”的研究。接下来探讨了他的研究对PBPD建模作为一门科学学科发展的意义。PBPD模型包含特定的表达式，以严格定量的方式表征暴露（以靶部位浓度表示）与药物效应（以生物学功能变化表示）之间因果路径上的过程。因果路径上的相关过程包括：（1）靶部位分布，（2）靶标结合与激活，以及（3）转导和稳态反馈。
