Impact of Changes in Free Concentrations and Drug-Protein Binding on Drug Dosing Regimens in Special Populations and Disease States.

Over the last few decades, scientists and clinicians have often focused their attention on the unbound fraction of drugs as an indicator of efficacy and the eventual outcome of drug treatments for specific illnesses. Typically, the total drug concentration (bound and unbound) in plasma is used in clinical trials to assess a compound's efficacy. However, the free concentration of a drug tends to be more closely related to its activity and interaction with the body. Thus far, measuring the unbound concentration has been a challenge. Several mechanistic models have attempted to solve this problem by estimating the free drug fraction from available data such as total drug and binding protein concentrations. The aims of this review are first, to give an overview of the methods that have been used to date to calculate the unbound drug fraction. Second, to assess the pharmacokinetic parameters affected by changes in drug protein binding in special populations such as pediatrics, the elderly, pregnancy, and obesity. Third, to review alterations in drug protein binding in some selected disease states and how these changes impact the clinical outcomes for the patients; the disease states include critical illnesses, transplantation, renal failure, chronic kidney disease, and epilepsy. And finally, to discuss how various disease states shift the ratio of unbound to total drug and the consequences of such shifts on dosing adjustments and reaching the therapeutic target.