Development of a nomogram for the estimation of long‐term adherence to clozapine therapy using neutrophil fluorescence

摘要

Aims Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow‐cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic–pharmacodynamic model relating FL3‐fluorescence to clozapine exposure and derived a nomogram for estimation of long‐term adherence. Methods Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an E max model to FL3‐fluorescence. FL3‐fluorescence was simulated for clozapine doses of 50, 150 and 400?mg daily ( n ?=?10 000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100?days) was compared to nomogram‐estimated adherence to evaluate the performance of the nomogram. Results The half‐life of FL3‐fluorescence was estimated at 228?h (coefficient of variation 35%). Median absolute prediction errors of the nomogram in case of fully random adherence for 50, 150 and 400?mg ranged from –0.193% to –0.525%. The nomogram performed slightly worse in case of nonrandom adherence (median prediction error up to 5.19%), but was still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3?weeks prior to FL3‐measurement. Conclusion Our nomogram could provide information regarding long‐term adherence based on prescribed clozapine dose and FL3‐fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram.