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

• Published in: The AAPS journal Vol. 21; no. 3; p. 40
• Main Authors: Pérez-Ruixo, Carlos, Remmerie, Bart, Peréz-Ruixo, Juan José, Vermeulen, An
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 14.03.2019
• Subjects: Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - therapeutic use; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Drug Monitoring - methods; False Negative Reactions; False Positive Reactions; Humans; Medication Adherence; Models, Biological; Pharmacology/Toxicology; Pharmacy; Predictive Value of Tests; Research Article; Risperidone - blood; Risperidone - pharmacokinetics; Risperidone - therapeutic use; ROC Curve; Schizophrenia - blood; Schizophrenia - drug therapy; drug plasma concentrations; population PK model–based simulation; drug adherence; diagnostic test; ROC analysis
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-019-0299-9

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.