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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 Emax 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.

BACKGROUND: Lithium can influence calcium homeostasis resulting in changes in parathormone set point and renal calcium handling. The clinical significance of these changes in older patients is unknown. The objective of this study was to investigate the possible association between duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion in older psychiatric patients corrected for renal function and vitamin 25OH D and also to estimate the point prevalence of hypercalcemia and raised parathormone. METHODS: A cross-sectional study of psychiatric outpatients visiting a specialized facility for older patients treated with lithium was performed. Patients underwent a comprehensive assessment and blood and urine testing. Potential confounders of calcium homeostasis were recorded. On the basis of the duration of lithium treatment, patients were divided into four groups. RESULTS: One hundred eleven patients were included, mean age 75.2 years. There was no significant association between the duration of lithium treatment and corrected calcium, parathormone and 24-h urinary calcium excretion. The point prevalence of hypercalcemia was 2.7% and 47.8% for raised parathormone. There was an unexpected but significant negative association between the duration of lithium treatment and vitamin 25OH D, with 76.9% vitamin 25OH D deficiency (

∗†Ingeborg Wilting, ‡Jan H. M. van Laarhoven, §Ingrid F. de Koning-Verest, and †‖Antoine C. G. Egberts ∗Department of Clinical Pharmacy, TweeSteden Hospital and St. Elisabeth Hospital, Tilburg; †Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Pharmacotherapy, Utrecht; ‡Department of Psychiatry, St. Elisabeth Hospital, and §Public Pharmacy de Blaak, Tilburg; ‖ Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht, The Netherlands