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. The area under the ROC curve (AUC) was used to identify the optimal C threshold. Single vs multiple C at steady state was also evaluated. After a single risperidone C measurement, the AUC (95% CI) was estimated to be 0.71 (0.69-0.72) and the optimal C threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple C measurements, the AUC (95% CI) increased up to 0.85 (0.84-0.87) for three C 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 measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.