Making Sense of Clozapine Levels: Plasma Ranges, NorClozapine Ratios, and Clinical Implications

Due to its complex metabolism, there are significant inter-and intra-individual variations in clozapine serum levels for a given dose.

Factors affecting clozapine levels:

• Inflammatory reactions through inhibition of CYP1A2
• Plasma Clozapine to Norclozapine (NOR) ratio increases at higher clozapine plasma concentrations in some patients (usually at > 600mcg/L)
• Caffeine can inhibit CYP1A2, but significantly high doses of caffeine are required to cause clinically significant change.
• CYP1A2 and CYP3A4 inducers or inhibitors.
• Serious respiratory infections can be associated with increases in plasma levels.
• Females tend to have higher concentrations of clozapine compared to males.

Efficacy : 

The consensus is that patients are more likely to respond above 350 mcg/L with a range between 250 and 420 mcg/L with a fall-off in clozapine response at levels above 450 mcg/L. [Ellison & Dufresne 2015]. 

Although some patients may respond at lower serum levels, it is recommended to achieve a level of at least 350 mcg/L before a patient is deemed a clozapine nonresponder.

Side Effects: 

• The range of serum levels that correspond with toxicity remains unclear.
• Haematological and cardiac events appear unrelated to serum level, while neurological side effects are more likely to correlate to serum level. Side effects are more likely at doses > 600mcg/L, with the risk of seizures increasing above 1000 mcg/L.
• A review of the use of clozapine levels to guide treatment and determine the cause of death found that the lowest effective clozapine levels ranged from 250 to 550 mcg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 mcg/L. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. [Stark & Scott, 2012]

Indications for therapeutic drug monitoring of clozapine are: 

• Signs of central nervous system toxicity
• Addition of a medication that can inhibit CYP1A2 or 3A4  [See article on pharmacogenomics for medications that can inhibit or induce these enzymes]
• Withdrawal of a medication or compound (polycyclic aromatic hydrocarbons) that can induce clozapine metabolism, e.g. smoking.
• Concerns of patient medication nonadherence
• Relapse of symptoms while maintained on a previously effective dose.

Clozapine: Norclozapine (NOR) ratio: [Ellison & Dufresne 2015]. 

• Norclozapine (NOR) has a longer half-life than its parent compound, and the Clozapine: Norclozapine level can have clinical utility.
• NOR is considered a less potent antagonist at adrenergic α1 and histamine H1 receptors than clozapine and is less likely to cause adverse effects such as orthostatic hypotension and sedation
• NOR has higher antagonistic activity at 5HT2C and 5HT2C antagonism is associated with clozapine-induced weight gain.
• Bone marrow toxicity for NOR is 10 times more potent than clozapine. [Stark & Scott, 2012]
• NOR has partial M₁ agonism, which increases acetylcholine in the medial prefrontal cortex and hippocampus, which, in turn, can promote increased executive functioning and memory
• It has been hypothesised that a clozapine: NOR ratio of two or more will increase the efficacy and tolerability of clozapine therapy.
• Lowering norclozapine levels by fluvoxamine augmentation (CYP1A2 inhibition) while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio with potential benefits of a reduction of side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy.in treatment-resistant patients with schizophrenia providing the rationale for fluvoxamine augmentation.  [Légaré et al., 2013]
• A low ratio (<0.5) suggests poor adherence in the previous 24 hours or rapid metabolism of the parent compound. 
• A high ratio (>3) could suggest inhibition of metabolism by a concomitant medication or saturation of metabolism.

Tobacco smoke contains polycyclic aromatic hydrocarbons that induce  CYP1A2 activity, which affects the metabolism of clozapine.

Pharmacokinetic studies have demonstrated more rapid clearance clozapine lower clozapine and norclozapine (desmethylclozapine) concentrations in smokers compared to nonsmokers. [Lowe & Ackman, 2010]

As few as five cigarettes, a day may be enough for enzyme system induction affecting clozapine levels. [Lowe & Ackman, 2010]

Smoking cessation leads to a rapid exponential decrease in CYP1A2 activity with a new steady state is reached in about 1 week. [Faber & Fuhr, 2004]

Smoking cessation can thus increase blood levels (> 50% increase), increasing the risk of toxicity with clozapine. [Meyer, 2001]

For a more detailed review on smoking and clozapine along with a clinical algorithm of management post smoking cessation read the article below.

READ MORE – Impact of Smoking on Clozapine Levels – Management of Smoking Cessation in Clozapine Treatment