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首页> 外文期刊>The Korean Journal of Physiology & Pharmacology >Potency and plasma protein binding of drugs in vitro—a potentially misleading pair for predicting in vivo efficacious concentrations in humans
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Potency and plasma protein binding of drugs in vitro—a potentially misleading pair for predicting in vivo efficacious concentrations in humans

机译：药物在体外的效价和血浆蛋白结合-一种潜在的误导性对，可预测人类体内的有效浓度

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摘要

In drug discovery or preclinical stages of development, potency parameters such as ICsub50/sub , K subi/sub, or K subd/sub in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, C submin/sub, etc.) in humans. However, to our knowledge, the fundamental assumption that the potency in vitro is correlated with the efficacious concentration in vivo in humans has not been investigated extensively. Thus, the present review examined this assumption by comparing a wide range of published pharmacokinetic (PK) and potency data. If the drug potency in vitro and its in vivo effectiveness in humans are well correlated, the steady-state average unbound concentrations in humans [ C subu_ss.avg/sub = f subu/sub·F·Dose/( CL ·τ) = f subu/sub·AUCss/τ] after treatment with approved dosage regimens should be higher than, or at least comparable to, the potency parameters assessed in vitro . We reviewed the ratios of C subu_ss.avg/sub/potency in vitro for a total of 54 drug entities (13 major therapeutic classes) using the dosage, PK, and in vitro potency reported in the published literature. For 54 drugs, the C subu_ss.avg/sub/ in vitro potency ratios were u/sub (unbound fraction), “ratio u/sub ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and f subu/sub should be avoided, especially for molecules with high protein binding.
机译：在药物发现或临床前开发阶段，通常使用体外效能参数，例如IC 50 ，K i 或K d 预测人体有效暴露的参数（AUC，C min 等）。然而，据我们所知，尚未广泛研究体外效力与人体内有效浓度相关的基本假设。因此，本综述通过比较广泛的已发表的药代动力学（PK）和药效学数据，检验了这一假设。如果人体内的体外药效和体内药效良好相关，则人体内的稳态平均未结合浓度[C u_ss.avg = f u ·F用批准的剂量方案治疗后的剂量/（CL·τ）= f u ·AUCss /τ]应高于或至少与体外评估的效能参数相当。我们使用已发表文献中报道的剂量，PK和体外效能，回顾了总共54种药物实体（13个主要治疗类别）的C u_ss.avg /效能的比率。对于54种药物，C u_ss.avg /体外效价比为u （未结合分数），“比率u ≤5％”;即31种药物中的28种）。因此，应避免仅使用体外效价数据和f u 预测人类体内的有效未结合浓度，尤其是对于具有高蛋白结合力的分子。

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