Preclinical PK & In Vitro ADME, Biogen Idec Inc., Cambridge, Massachusetts 02142, USA.
J Pharm Sci. 2013 Sep;102(9):2953-94. doi: 10.1002/jps.23614. Epub 2013 Jun 24.
The importance of plasma protein binding (PPB) in modulating the effective drug concentration at pharmacological target sites has been the topic of significant discussion and debate amongst drug development groups over the past few decades. Free drug theory, which states that in absence of energy-dependent processes, after steady state equilibrium has been attained, free drug concentration in plasma is equal to free drug concentration at the pharmacologic target receptor(s) in tissues, has been used to explain pharmacokinetics/pharmacodynamics relationships in a large number of cases. Any sudden increase in free concentration of a drug could potentially cause toxicity and may need dose adjustment. Free drug concentration is also helpful to estimate the effective concentration of drugs that potentially can precipitate metabolism (or transporter)-related drug-drug interactions. Disease models are extensively validated in animals to progress a compound into development. Unbound drug concentration, and therefore PPB information across species is very informative in establishing safety margins and guiding selection of First in Human (FIH) dose and human efficacious dose. The scope of this review is to give an overview of reported role of PPB in several therapeutic areas, highlight cases where PPB changes are clinically relevant, and provide drug metabolism and pharmacokinetics recommendations in discovery and development settings.
在过去几十年中，药物开发团队一直在讨论和争论血浆蛋白结合（PPB）在调节药理靶部位有效药物浓度方面的重要性。游离药物理论指出，在没有能量依赖过程的情况下，达到稳态平衡后，血浆中的游离药物浓度等于组织中药理靶受体的游离药物浓度，该理论已被用于解释大量情况下的药代动力学/药效学关系。药物游离浓度的任何突然增加都可能导致毒性，可能需要调整剂量。游离药物浓度还有助于估计可能引发代谢（或转运体）相关药物相互作用的药物的有效浓度。疾病模型在动物中得到广泛验证，以推进化合物进入开发阶段。在建立安全性裕度和指导选择首次人体（FIH）剂量和人体有效剂量方面，跨物种的未结合药物浓度（因此也是 PPB 信息）非常有意义。本文综述的范围是概述 PPB 在几个治疗领域中的作用，强调 PPB 变化具有临床相关性的情况，并在发现和开发环境中提供药物代谢和药代动力学建议。
