Toutain P L, Lees P
UMR 181 Physiopathologie et Toxicologie Expérimentales INRA/ENVT, Ecole Nationale Vétérinaire de Toulouse, Toulouse cedex 03, France.
J Vet Pharmacol Ther. 2004 Dec;27(6):467-77. doi: 10.1111/j.1365-2885.2004.00613.x.
In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.
在兽药研发过程中，药代动力学（PK）和药效学（PD）数据通常是在单独的平行研究中确定的，以协助设计剂量方案，以便在临床试验中进行后续评估。本综述介绍了PK/PD建模的概念，即一种在同一研究中生成PK和PD数据，并根据药物血浆浓度推导PD参数数值的方法。PD参数定义了浓度-效应关系的疗效、效价和斜率（敏感性）。有人提出，从PK/PD建模中得出的参数可作为剂量滴定研究的替代且更优方法，用于选择合理的给药方案（剂量和给药间隔），以便在临床试验中进行进一步评估。在PK/PD建模中，效应的解释变量是血浆浓度曲线。与剂量范围研究相比，PK/PD方法相对于剂量滴定研究具有多个优势，剂量范围研究根据定义需要测试多个剂量，而PK/PD方法通过研究单一剂量即可确定预计的给药方案。目前，兽药研发过程中PK/PD建模的实施受到迄今为止开展的兽医研究数量有限的限制，因此对PK/PD概念的理解有限，且监管机构指南中也未提及。尽管如此，PK/PD建模在确定合理给药方案方面具有巨大潜力，因为它考虑并量化了种间变异性的两个主要来源（PK和PD）。因此，它适用于种间外推和多物种药物研发。除了目前兽医科学界对PK/PD原理的认识有限外，实施PK/PD建模的另一个限制是需要验证PK/PD方法，从而使制药公司和监管机构对其价值有信心。
