Drug resistance with monitored adherence

Drug resistance can be defined as the failure of a drug to exert its expected effect on pharmacological biomarkers and is caused by pharmacogenetic, cellular or clinical factors. Non-adherence, a common challenge in chronic outpatient therapy, and drug drug interactions (DDI) constitute two major clinical factors that contribute to drug resistance. Both can be controlled by a new technology for electronic multidrug adherence monitoring that was developed in the framework of this thesis.
In a first project, we studied the prevalence of unreached biomarker targets in a retrospective population-based cross sectional study on 4380 patients with lipid-lowering drugs (LLD) and/or antihypertensive treatment (AHT). The observed rates of missed target attainment (25.8% for LLD and 36.3% for AHT) can serve as estimates of the burden of drug resistance in an unselected outpatient population. Co-morbidity, clinical and pharmacogenetic factors are presumed contributors to resistance, but could not be specifically analysed in this retrospective analysis.
A prospective assessment of potential factors to resistance was integrated in the design of the main study of this thesis. Outpatients with antiplatelet therapy were studied with the polymedication adherence monitoring system (POEMS), which allowed tracking the patients’ adherence to all his oral solid drugs. In vitro platelet aggregation was measured before and after a weeklong period of monitored adherence. Additionally, pharmacogenetic and clinical data was collected to analyse the impact of the presumed contributors to drug resistance. The evaluable patients (N=82) were analysed separately in two overlapping samples of 69 aspirin and 32 clopidogrel users. Resistance with monitored adherence was found in 20% of the aspirin users and 25% of the clopidogrel users. Non-adherence could be dismissed as a major contributor to antiplatelet drug resistance in chronic outpatient treatment due to the absence of significant differences of platelet aggregation before and after adherence monitoring. Multidrug adherence monitoring with POEMS revealed that the actual exposure to proton pump inhibitors was too low to analyse the effect of its potential DDI with clopidogrel. The significance of the controversial DDI between high-dose lipophilic statins and clopidogrel was supported by the finding that patients with staggered intake of these potentially interfering drugs was associated with better platelet inhibition than concomittant intake. Significant effects on aspirin resistance were found for diabetes mellitus and systemic inflammation. These factors were also most probable to have an impact on resistance with clopidogrel, while no effect could be observed by the presence of a CYP2C19 poor metabolizer genotype.
In a sub-analysis of the main study, POEMS proved to be a suitable tool to collect comprehensive data on multidrug timing adherence. Median intake times of 7:41 h, 12:09 h and 18:36 h were observed for the morning, midday and evening doses. Particularly in working patients, significant delays of the morning drug intake times were observed on weekends. The time variability of drug intake (tVAR) was generally lower in the morning than in the evening. A tendency towards lower LDL-C values in patients with a lower tVAR of the LLD containing dose was observed, suggesting that their effectiveness may depend on the precision of timing adherence. Multidrug adherence measurement may serve as a useful diagnostic tool to disclose the pattern of timing adherence beyond subjective measures of adherence (e.g. Morisky Medication Adherence Scale MMAS; Beliefs about Medicines Questionnaire BMQ). POEMS proofed to be useful for the diagnosis of aberrant timing in adherence in individual patients. The irrational pattern of timing, the intervention of a pharmacist and adherence during follow-up were described in an extended case report of a patient that was observed in the course of the main study
Given the evident relationship between objectively measured adherence and drug effectiveness, POEMS was finally integrated in the design of a further prospective study aimed at comparing oral vs. intramuscular vitamin B12 substitution.
In conclusion this thesis showed that the investigation of antiplatelet resistance with prospective adherence monitoring to all oral solid drugs is feasible and well accepted by the patients. Aspirin and clopidogrel resistance rates were not significantly affected by adherence monitoring. Additionally, adherence data collected with POEMS allowed a more precise analysis of potential DDIs. Associations between timing adherence to LLD and their lipid lowering effects supported a potential impact of the temporal pattern of drug intake on drug effectiveness. These findings underline the need to consider objectively measured timing adherence to control for the diluting effect of non-adherence on drug efficacy and to study drug drug interactions based on adherence data.