Clozapine to Norclozapine Ratio Calculation
The clozapine to norclozapine ratio is calculated by dividing the plasma clozapine concentration by the plasma norclozapine concentration (clozapine level ÷ norclozapine level), typically measured from trough blood samples drawn 12 hours after the last dose.
How to Calculate the Ratio
- Obtain trough plasma levels of both clozapine and norclozapine from blood drawn immediately before the next scheduled dose 1
- Divide the clozapine concentration by the norclozapine concentration to obtain the ratio 2
- For example, if clozapine = 500 ng/mL and norclozapine = 250 ng/mL, the ratio = 500 ÷ 250 = 2.0 2
Normal Ratio Values and Clinical Interpretation
- The median clozapine:norclozapine ratio is approximately 1.25 at lower clozapine concentrations (<350 ng/mL) 2
- At therapeutic clozapine concentrations (350-550 ng/mL), the median ratio increases to approximately 2.08 at concentrations >1.0 mg/L 2
- A ratio greater than 2 suggests either:
Clinical Significance of the Ratio
- The ratio increases with higher clozapine concentrations because the metabolic pathway becomes saturated, meaning the enzyme system (CYP1A2) cannot keep up with converting clozapine to norclozapine at higher doses 2
- This saturation effect is particularly important when smoking status changes, as smoking induces CYP1A2 and significantly affects clozapine metabolism 2
- An abnormally high ratio may indicate recent dose ingestion rather than a true trough level, which could lead to incorrect dose adjustments 2
Practical Monitoring Considerations
- Both clozapine and norclozapine should be measured simultaneously to calculate the ratio and assess total drug exposure 3, 2
- Either serum or plasma can be used for measurement, as they show high correlation (r = 0.996) with only approximately 7% difference, which reduces to 3% when corrected for hematocrit 4
- The ratio helps distinguish adherence issues from metabolic variations, as non-adherent patients may show unusual ratio patterns 2