Use of the law of mass action for predicting free levels of antiepileptic drugs in serum.

The estimation of non-protein-bound levels (free levels) of antiepileptic drugs in serum is considered a useful adjunct in the management of patients with epilepsy. However, present methods for separating free levels e.g., by equilibrium dialysis and ultrafiltration are too laborious to be used routinely except in special centers. Thus this thesis has focused on the development and validation of a set of formulae, based on the Law of Mass Action, for use in predicting free levels of phenytoin, carbamazepine and phenobarbitone in patients on monotherapy and polytherapy from serum total drug and albumin levels. This work has comprised:- (i) Establishing a micromethod for the separation of free antiepileptic drugs in serum by ultrafiltration. (ii) Developing a high performance liquid chromatography micromethod for the determination of free and total antiepileptic drugs in serum. (iii) Developing a theoretical framework for the prediction of free drug levels in serum for patients on monotherapy and polytherapy. (iv) Investigating the effect of temperature on the binding of drugs to serum albumin. (v) Establishing temperature-related therapeutic ranges for free drug levels. (vi) Evaluating the quality of the predicted versus measured free drug levels at the physiological temperature. (vii) Comparing the performance of the derived predictive method with that of previous methods based on statistical concepts. The investigation has demonstrated:- The feasibility of predicting free drug levels in patients on monotherapy or polytherapy from serum total drug and albumin levels at the physiological temperature. The methodology developed would allow routine laboratories to provide an estimate of free drug levels in addition to measured total drug levels, thus potentially improving the therapeutic drug monitoring service for the management of patients with epilepsy