Nifedipine May Be an Inhibitor of Clozapine Metabolism as Seen in 5 Patients: 2 From a US Double-Blind Study and 3 From a German Therapeutic Drug Monitoring Study

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BACKGROUND: Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications. METHODS: We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition. RESULTS: In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity. CONCLUSIONS: In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.

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