A Receiver Operating Characteristic Framework for Non-adherence Detection Using Drug Concentration Thresholds-Application to Simulated Risperidone Data in Schizophrenic Patients

Non-adherence to antipsychotic medication is a primary factor in disease relapse in schizophrenic patients. We sought to evaluate if plasma concentrations of the antipsychotic risperidone can be used as a predictor of treatment adherence and to identify the optimal plasma concentration threshold to reliably distinguish between adherent and non-adherent patients. A population pharmacokinetic model was used to simulate plasma risperidone steady-state trough concentrations in 1000 virtual patients, where 60% of the patients were 100% adherent to their medication, while 40% of the patients were non-adherent to their medication. The probability of adherence was assessed by receiver operating characteristic (ROC) analysis on C_trough. The area under the ROC curve (AUC_ROC) was used to identify the optimal C_trough threshold. Single vs multiple C_trough at steady state was also evaluated. After a single risperidone C_trough measurement, the AUC_ROC (95% CI) was estimated to be 0.71 (0.69-0.72) and the optimal C_trough threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple C_trough measurements, the AUC_ROC (95% CI) increased up to 0.85 (0.84-0.87) for three C_trough measurements. The optimal probability threshold to reliably discriminate between adherent and non-adherent patients was estimated to be 0.51. Using this model which is reflective of typical adherence to antipsychotic medication, we found that three consecutive steady-state C_trough measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.