How do I interpret clozapine or norclozapine blood, serum or plasma levels; What do these mean?

Rationale for Clozapine Levels

Blood levels of medications (serum or plasma) are used because, compared with oral dosage, they correlate more closely with medication concentration in the brain. With regard to clozapine, blood levels are available for clozapine, and for norclozapine, the major active clozapine metabolite.

Levels should not be the primary determinant of dosage, but can play an important role in guiding treatment, in conjunction with clinician assessment of symptoms and side effects.

There are situations when a clozapine level can be useful: to assess medication adherence, when clozapine is less effective than expected, when there are more side effects than expected, or when medication interactions are suspected.  Additionally, clozapine levels can be helpful for special populations, like older adults, children or adolescents, people with intellectual disabilities, people with hepatic impairment, or women who are pregnant. Levels can be useful when there are changes that might be affecting P450 metabolism, such as stopping or starting smoking around hospital admissions.

Timing of Clozapine Levels

Levels should be a steady state, trough level.  Clozapine reaches a steady-state concentration at 5-7 days. Levels should be drawn 12 hours (± 2 h) after the last dose.

Relationship between Clozapine Levels and Efficacy

Clozapine blood levels are correlated with both clozapine effectiveness and side effects. However, there is large variation between patients in blood levels. There is also substantial variation within patients (plus or minus 30% in some studies). Given the inter-patient variability, there is no minimum effective clozapine level and no maximum safe level. The mean threshold response for people with treatment resistant schizophrenia is 350 ng/ml. If a patient still has positive symptoms and has a clozapine level <350 ng/mL, prescribers should consider increasing the clozapine dose to correspond with a level >350 ng/ml. Patients rarely respond to levels >1000 ng/ml.

High Clozapine Levels (>1000 ng/ml)

If a clozapine level is unexpectedly high, evaluate the patient for dose-related side effects. If there is clozapine toxicity, the patient should obtain urgent care that includes symptomatic treatment and assessment for serious problems such as cardiac arrhythmias, seizure activity, or systemic infection. If the patient has no signs of toxicity, possibilities include lab error, a non-trough blood draw, a safe level for this patient, or inhibition of P450 metabolic enzymes from changes in other medications or smoking. Evaluate and consider whether to recheck the level. See separate clinical tip on the seizure side effect of clozapine.

Norclozapine Levels

Norclozapine levels are often performed at the same time as clozapine levels. Norclozapine is an active metabolite that differs from clozapine in efficacy and side effects and has a longer half-life. Most agree that clozapine levels best correlate to efficacy. Norclozapine levels are useful to calculate the MR ratio (see below), which can be helpful in understanding clozapine’s metabolism.

Using the Metabolic (MR) Ratio

Guidelines for Interpreting the Metabolic Ratio (MR) utilize the clozapine to norclozapine ratio. Obtaining the MR ratio early in treatment might help you better understand clozapine’s kinetic properties for your individual patient. The MR ratio for any patient is genetically fixed and would only change based on changes in smoking behavior, changes in other meds, etc.

1. MR = 1.32: The expected mean value for nonsmokers who are CYP 1A2 extensive metabolizers (Meyer & Stahl, 2020). Other reviews of evidence have found a value of 1.73 to the normal MR (Schoretsanitis, 2019).
2. MR << 1.00: Trough values of 1.00 or less reflect exposure to an inducer (e.g. smoking, phenytoin), or CYP 1A2 ultrarapid metabolizer status. We might also expect to see a drop in the MR ratio with a decrease in the clozapine level for someone who has been partially non-adherent (keeping in mind clozapine has a shorter half-life than norclozapine).
3. MR >> 1.32: Trough values greater than 2.00 reflect exposure to inhibitors of the main CYP enzymes involved in clozapine metabolism: 1A2, 2C19, 2D6 or 3A4, or poor metabolizer status, especially at CYP 1A2 or CYP 2D6. As clozapine is principally metabolized via CYP 1A2, strong CYP 2D6 or 3A4 inhibitors will typically increase clozapine levels by 40% – 100%, generating MR values in the range of 1.80 to 2.60. Conversely, strong 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) may increase clozapine levels up to 10-fold, with resulting MR values of 3.00 or greater. CYP poor metabolizers will typically have MR values comparable to those seen with use of strong 2D6 or 3A4 inhibitors.
4. MR =/> 3.0 during medical illness: A marked increase in MR from baseline in the context of serious bacterial or viral infections may occur, with MR values on average around 3.0 (range 1.4 – 8.6). This change in clozapine metabolism reflects an inhibitory effect of inflammatory cytokines on CYP 1A2 activity.

REFERENCES

• Meyer, J.M. & Stahl, S.M. (2020). The clozapine handbook. Cambridge University Press.
• Nielsen J, et al. (2013). Termination of clozapine treatment due to medical reasons: When is it warranted and how can it be avoided? Journal of Clinical Psychiatry, 74, 603-613.
• Schoretsanitis, G., Kane, J.M., Ruan, C.-J., Spina, E., Hiemke, C. (2019). A comprehensive review of the clinical utility of  and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Review of Clinical Pharmacology, 12(7), 603-621. doi: 10.1080/17512433.2019.1617695
• Williams, A.M. & Park, S.H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29, 101-111.