Consideration of capilary electrophoresis as an analysis technique for the intended application of therapeutic drug monitoring of antipsychotics

The use of therapeutic drug monitoring (TDM) when prescribing antipsychotics is not yet considered a routine care procedure, despite evidence and opinion regarding its benefit. Amongst the arguments against the inclusion of TDM, are the many logistical deficiencies that prevent the TDM service from being as optimal as warranted. It has been identified that improvements within the service being offered for TDM may result in improvements with the overall TDM practice; which may result in an increase usage. It was recognised that altering the analysis technique to a faster, more versatile process, may be impacting on the overall service that could be offered and thus improve the holistic practice of TDM of antipsychotics. Capillary electrophoresis (CE) was chosen for consideration as an alternate analysis technique, primarily due to the known ability of this technique to achieve fast separations of structurally similar compounds and its ability to be readily implemented in small potentially portable lab-on-a-chip devices. It was therefore the aim of this thesis to develop and consider CE methods for the analysis of antipsychotics for the intended application of TDM. The development of CE methods was performed in a step-wise manner, through an understanding of the applications use. The first method developed was aimed at a secondary application of TDM of compliance monitoring and achieved through an extensive examination of a multivariate optimisation of separation parameters using the modelling software known as Peakmaster. Through this work a set of parameters was identified that allowed for the separation of 17 antipsychotics within 5 minutes. The optimal method was subsequently validated for evaluation and found to be analytical suitable for consideration within a compliance monitoring setting. In addition, the developed separation was successfully adapted for compatibility with a mass spectrometer detector (CE-MS), however this was not considered appropriate for clinical application at this stage due to instrumental weakness observed during this work. The second stage of focus was to progress the method development specifically towards TOM appropriate applications. This was achieved by developing the first separation for aripiprazole and both main metabolites. Here a separation was achieved for three structurally similar compounds within nine minutes and found to be ideal for the intended application of TOM. Having successfully developed aCE method suitable for TOM, the final method was developed with the aim of incorporating the two positive elements of the prior two methods: many compounds within one method and achieve separation of structurally similar compounds. Consequently a method was developed incorporating five popularly prescribed antipsychotics and metabolites, resulting in a separation of 13 compounds within eight minutes. The methods developed and presented within this thesis were considered suitable for the intended application of TOM. Due to the speed and resolution achieved within the separations, it was foreseeable that the implementation of these methods would have the potential of improving the versatility of the TOM service and therefore potentially improve the usage of TOM for antipsychotics. It was clearly acknowledged that further assessment would be necessary (such as tandem testing) before suggesting these methods be implemented. However the work here supports the idea of changing the analytical technique employed for the process of TOM of antipsychotics to CE, as a modification that would allow for improvements to the overall service delivered