From the Guidelines
The recommended plasma levels for clozapine (Clozaril) are ≥350 ng/ml, which constitutes an optimum threshold requirement for establishing non-response to clozapine treatment. This is based on the most recent and highest quality study available, which emphasizes the importance of measuring trough serum levels of clozapine on at least two occasions separated by at least a week at a stable dose of clozapine 1. The study highlights that clozapine levels ≥350 ng/ml are associated with better clinical response, and it is strongly recommended that levels are used to establish adherence and response to treatment.
Key Considerations
- The minimum effective concentrations are generally considered to be around 250 ng/mL, but levels above 350 ng/mL are associated with better clinical response.
- Blood level monitoring should be performed regularly, especially during dose adjustments, with trough levels (drawn 12 hours after the last dose) providing the most consistent measurements.
- Plasma concentrations above 600-700 ng/mL are associated with increased risk of seizures and other adverse effects without additional therapeutic benefit.
- Individual patient response varies, so treatment should be personalized based on clinical response and tolerability.
- Factors affecting clozapine levels include smoking status (smokers typically require higher doses), age, gender, and concurrent medications that inhibit or induce CYP1A2, the primary enzyme responsible for clozapine metabolism.
Clinical Implications
- Clinicians should aim to achieve plasma levels of ≥350 ng/ml when treating patients with treatment-resistant schizophrenia.
- Regular blood level monitoring is crucial to ensure optimal therapeutic effect and minimize the risk of adverse effects.
- Dose adjustments should be made based on clinical response and tolerability, taking into account the individual patient's factors that may affect clozapine levels.
- The study by Howes et al. 1 provides the most up-to-date and reliable guidance on clozapine plasma levels, and its recommendations should be followed in clinical practice.
From the FDA Drug Label
Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2. 5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing.
The recommended plasma levels for clozapine are between 102 ng/mL and 771 ng/mL for peak concentrations and between 41 ng/mL and 343 ng/mL for minimum concentrations at steady state, as observed with a dose of 100 mg twice daily 2.
From the Research
Recommended Clozapine Plasma Levels
The recommended plasma levels for clozapine are as follows:
- A range between 250 and 550 ng/mL could be recommended, while noting that a level of >350 ng/mL is the most optimal for response 3
- Plasma trough levels above a therapeutic threshold of 350-400 micro g/L have been associated with a significantly higher response rate 4
- A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70% 5
- Plasma concentrations above 350 ng/mL have been found to maximize clinical response in treatment-refractory schizophrenic patients 6, 7
Key Findings
- The interquartile range for treatment response was 223-558 ng/mL 3
- Clozapine dose should be optimised based on clozapine therapeutic levels, rather than dose or clozapine concentration to dose ratio 3
- Some patients may require dosages higher than 900 mg/day to achieve optimal plasma levels, especially young male smokers 4
- The incidence of side effects is higher at clozapine concentrations above 350 ng/ml, and increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations 5