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Review Article

Korean J Physiol Pharmacol 2019; 23(4): 231-236

Published online July 1, 2019 https://doi.org/10.4196/kjpp.2019.23.4.231

Copyright © 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

Dong-Seok Yim1,2,*

1Department of Clinical Pharmacology and Therapeutics, The Catholic University of Korea, Seoul St. Mary’s Hospital, 2PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

Correspondence to:Dong-Seok Yim
E-mail: yimds@catholic.ac.kr

Received: December 27, 2018; Revised: April 28, 2019; Accepted: April 30, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In drug discovery or preclinical stages of development, potency parameters such as IC50, Ki, or Kd in vitro have been routinely used to predict the parameters of efficacious exposure (AUC, Cmin, 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 [Cu_ss.avg = fu·F·Dose/(CL· τ) = fu·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 Cu_ss.avg/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 Cu_ss.avg/in vitro potency ratios were < 1 for 38 (69%) and < 0.1 for 22 (34%) drugs. When the ratios were plotted against fu (unbound fraction), “ratio < 1” was predominant for drugs with high protein binding (90% of drugs with fu ≤ 5%; i.e., 28 of 31 drugs). Thus, predicting the in vivo efficacious unbound concentrations in humans using only in vitro potency data and fu should be avoided, especially for molecules with high protein binding.

Keywords: In vitro, Potency, Unbound concentration

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