A Receiver Operating Characteristic Framework for Non-adherence Detection Using Drug Concentration Thresholds—Application to Simulated Risperidone Data in Schizophrenic Patients
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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 Ctrough. The area under the ROC curve (AUCROC) was used to identify the optimal Ctrough threshold. Single vs multiple Ctrough at steady state was also evaluated. After a single risperidone Ctrough measurement, the AUCROC (95% CI) was estimated to be 0.71 (0.69–0.72) and the optimal Ctrough threshold accounting for the lowest number of adherent and non-adherent misclassifications was estimated to be 11.9 ng/mL. After multiple Ctrough measurements, the AUCROC (95% CI) increased up to 0.85 (0.84–0.87) for three Ctrough 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 Ctrough measurements are needed for an accurate and precise diagnostic test to discriminate between patients who are adherent or non-adherent to treatment.
KEY WORDSdiagnostic test drug adherence drug plasma concentrations population PK model–based simulation ROC analysis
Stacey E. Shehin, Ph.D. (PRA Health Sciences) provided medical writing assistance, which was funded by Janssen Research & Development. Harry Ma, Ph.D. (Janssen Global Services) provided additional editorial support. Portions of this study have been previously presented at the Population Approach Group of Europe’s 26th Annual Scientific Meeting, June 6–9, 2017, Budapest, Hungary. All authors meet ICMJE criteria, had full access to the study data, and take responsibility for integrity of the data.
This study was funded by Janssen Research & Development, LLC.
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Conflict of interest
All authors are employees of Janssen Research & Development, LLC, and may hold stock options or shares in the company.
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