Application of microsampling methods to cardiovascular medication adherence assessment

Cardiovascular disease remains the number one killer globally. However, adherence to medication is a major health problem. It has been reported that 50% of cardiovascular patients do not adhere to treatment. This level of nonadherence results in poor health outcomes for the patient, hospital readmissions and avoidable deaths. Wasted and unused medicines cost the National Health Service up to £4 billion annually. Commonly used methods of assessing adherence to therapy in clinical practice such as self-report, pill counting, pharmacy refill and claims data log and electronic monitors are subjective, based on proxy evidence, hence not effective. Blood drug concentrations are associated with effectiveness of the treatment and is therefore a good marker for cases of nonadherence. However, plasma and serum analysis require blood sampling by venepuncture which is highly invasive and large volumes of blood (1 – 5ml) to produce enough sample for analysis. Microsampling methods offer a cost-effective alternative to self-collect finger prick blood samples for the determination of drug levels to indicate adherence to medication. The work undertaken in this thesis describes the development, validation and application of a microsampling based liquid chromatography – high resolution mass spectrometry (LC-HRMS) assay for simultaneous determination of eleven candidate cardiovascular drugs to indicate adherence to medication. The target drugs include amlodipine, atenolol, atorvastatin, bisoprolol, diltiazem, doxazosin, lisinopril, losartan, ramipril, simvastatin, and valsartan. The LC-HRMS method was validated, with results for accuracy and precision within acceptable limits; analytes were stable at room temperature in dried blood format for at least 8 weeks and hematocrit values had no significant effect. The LC-HRMS assay was used to analyse 850 dried blood samples from 141 volunteers, some of whom were prescribed one or more of the target drugs. The assay successfully identified volunteers who were known to be either adherent or nonadherent; confirmed the correct drug/drugs for multiple prescriptions; and revealed several examples of unsuspected nonadherence. These results demonstrate the possible application of microsampling based LC-HRMS assays for therapeutic drug monitoring of cardiovascular disease drugs in routine clinical practice.