Rationale for monitoring free drug levels

Recent developments in our knowledge of drug binding prompt the questions, in what circumstances are measurements of free levels necessary, desirable or not warranted? Free level monitoring should be considered for drugs for which the usefulness of plasma level monitoring has been established, drugs which are highly bound to plasma proteins, and which exhibit a variable free fraction. In terms of drug distribution, free drug concentration is independent of free fraction, while total concentration is a resultant of free concentration and free fraction. For drugs with a low extraction ratio, the total concentration at steady-state depends upon free fraction, but the free concentration is independent of free fraction. With high extraction ratio drugs, the free concentration is dependent upon free fraction but only after parenteral administration. There are numerous examples of drugs which are highly bound and exhibit large variations in free fraction. Free fraction may increase with drug concentration. Pathophysiological changes in the binding ligands, albumin and alpha 1-acid glycoprotein, as well as changes in the concentration of endogenous compounds which compete for binding sites, may also cause changes in free drug fraction. Binding interactions resulting from polytherapy may also result in a variable free fraction. Ultrafiltration devices now enable the convenient and accurate determination of free drug levels. Areas in which this should prove useful are investigations of concentration-effect relationships and clinical situations requiring intensive monitoring where binding changes are suspected.