What is known about norclozapine blood levels for patients taking clozapine?

The primary interpretation of clozapine blood levels is done using the clozapine level itself (see this SMI Adviser tip). However, norclozapine is the principal metabolite of clozapine, and is pharmacologically active. Most laboratories provide norclozapine levels when a clozapine plasma concentration is ordered, but there may be a few labs that require a separate order. Although there have been extensive studies of the correlation between norclozapine levels and efficacy and safety outcomes, for now the primary use of norclozapine levels is to explore how a patient metabolizes clozapine. This is typically assessed by calculating the ratio of clozapine to norclozapine at steady state based on a 12-hour trough. This ratio is the metabolic ratio or MR. In a large study of 9894 samples from 3782 patients, the mean MR of all samples was 1.32 (Rostami-Hodjegan et al., 2004) but values vary widely in the literature (range 1.19 to 3.37), depending on the sample source (Schoretsanitis et al., 2019).

MR values < 1.00 reflect ultra-rapid metabolism via cytochrome P450 (CYP) 1A2, the smoking of tobacco cigarettes or use of cytochrome P450 inducers (e.g. carbamazepine). See this SMI Adviser tip for more information on medication interactions is available. MR values > 2.00 can be seen in CYP1A2 poor metabolizers or with the use of P450 inhibitors. Assuming the trough level is obtained roughly 12 hours after the last dose, there should be no change in the MR as long as the patient has not started smoking (which will lower the MR), stopped smoking or switched from tobacco cigarettes to vaping (which will raise the MR), or had CYP inhibitors or inducers added or removed.  Thus, deceases in clozapine plasma levels without a change in MR reflect poor medication adherence. Conversely, a patient who starts smoking will not only lower the plasma clozapine level by as much as 50%, but also lower the MR. This knowledge can be useful when patients transition from nonsmoking facilities to outpatient care where smoking is permitted. It will help the clinician decide whether lower outpatient clozapine levels are a product of poor adherence or the resumption of smoking.

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