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

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 PK/PD 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 analyzed using non-linear mixed effects modelling. A previously described PK 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 hours (coefficient of variation 35%).. Median absolute prediction errors (PE) 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 non-random adherence (median PE up to 5.19%), but 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.

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