Identifying lack of adherence to antipsychotic treatment using plasma concentrations measurements
Carlos Perez-Ruixo (1), Bart Remmerie (1), Juan Jose Perez-Ruixo (1), and An Vermeulen (1)
(1) Janssen R&D, Beerse, Belgium.
Objectives: To evaluate if measuring antipsychotic plasma concentrations using a diagnostic test can be used as a predictor of treatment adherence, and to identify the best plasma concentration threshold to reliably discriminate between adherent and partially non-adherent patients with schizophrenia.
Methods: A population pharmacokinetic model for risperidone was used to simulate plasma risperidone active moiety (risperidone + active metabolite 9-hydroxyrisperidone) trough concentrations (Ctrough) for an oral dose of 4 mg under two different scenarios. The first scenario assumed that all subjects had been adherent to their medication all of the time, whereas the second scenario assumed that 40% of the subjects had been non-adherent to their treatment, and randomly missed 20% to 50% of their doses over time at steady-state.[1] Based on Ctrough, measured 24 hours after the last dose, the probability of being an adherent patient was calculated and assessed as a predictor of drug-treatment adherence by performing a receiver operating characteristic (ROC) analysis among the simulated patients under the two scenarios.[2,3] The area under the ROC curve (AUCROC), sensitivity (SEN), specificity (SPE), positive (PPV) and negative (NPV) predictive values were calculated and an assessment of the utility of multiple (vs single) drug concentrations of the diagnostic test was conducted.[4]
Results: The median (CV%) Ctrough for the non-adherent cohort was 9.5 ng/mL (81.7%) while the median (CV%) Ctrough for the adherent cohort was 16.3 ng/mL (64.1%). The AUCROC, SEN, SPE, PPV and NPV (95%CI) were estimated to be 0.71 (0.69-0.72), 0.71 (0.69-0.73), 0.60 (0.58-0.63), 0.74 (0.72-0.76) and 0.56 (0.54-0.59) respectively, while the optimal predictive Ctrough threshold accounting for the lowest number of misclassifications was 11.9 ng/mL. After the inclusion of 2 additional steady-state Ctrough measurements as predictors, the AUCROC, SEN, SPE, PPV and NPV (95%CI) were estimated to be 0.85 (0.84-0.87), 0.92 (0.91-0.93), 0.66 (0.63-0.68), 0.81 (0.79-0.83) and 0.83 (0.81-0.85) respectively, while the optimal predicted probability threshold to reliably discriminate between adherent and non-adherent patients was estimated to be 0.51.
Conclusions: The inclusion of 3 drug concentrations measurements provides an accurate and precise diagnostic test which enables to properly discriminate between adherent and non-adherent patients, if the non-adherent patients are missing at least 20% of the dose intakes.
References:
[1] Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002; 63: 892-909.
[2] Zweig MH, Campbell G. Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem. 1993; 39: 561-77.
[3] Altman DG, Bland JM. Diagnostic tests 2: predictive values. BMJ 1994; 309: 102.[4] Greiner M, Pfeiffer D, Smith RD. Principles and practical application of the receiver operating characteristic analysis for diagnostic test. Prev Vet Med 2000; 45: 23-41.
