Problems in therapeutic drug monitoring: free drug level monitoring.

Historically, it has been assumed that only free drug concentration is the pharmacologically active species. This article reviews the theoretical pharmacological and pharmacokinetic justifications for monitoring free drug levels. The determinants likely to influence plasma protein binding and the free concentrations of drugs are delineated. The different methods which can be used for determining free drug level are presented. Their advantages and drawbacks as well as their reliability and suitability for routine clinical practice are discussed. Currently, antiepileptic drugs such as valproic acid, phenytoin, carbamazepine and a few antiarrhythmic drugs meet the theoretical criteria justifying free drug level monitoring. Conditions causing alteration in free concentrations of these drugs are reported. But, for all these drugs, there is a considerable lack of data establishing the correlations between therapeutic or toxic response and free concentration. Presently, our capability to interpret correctly the free drug level data is still limited. In the future, much more effort must be devoted in order to provide sufficient information on the clinical relevance of free drug concentration.