Calculating the Norclozapine to Clozapine Ratio
The norclozapine to clozapine ratio is calculated by dividing the plasma norclozapine concentration by the plasma clozapine concentration (both measured in the same units, typically ng/mL or mg/L), obtained from a trough blood sample drawn 12 hours after the last dose.
Calculation Method
- Obtain trough blood levels of both clozapine and norclozapine from a sample drawn 12 hours after the last clozapine dose, before the next scheduled dose 1
- Divide the norclozapine concentration by the clozapine concentration to obtain the ratio 2
- For example: If clozapine = 400 ng/mL and norclozapine = 200 ng/mL, the norclozapine:clozapine ratio = 200/400 = 0.5 (or expressed inversely as clozapine:norclozapine ratio = 2.0) 2
Clinical Interpretation of the Ratio
Normal Range
- The median norclozapine to clozapine ratio is approximately 0.8 (or clozapine:norclozapine ratio of 1.25) at therapeutic clozapine concentrations below 350 ng/mL 2
- At higher therapeutic clozapine concentrations (>1000 ng/mL), the median ratio shifts to approximately 0.48 (or clozapine:norclozapine ratio of 2.08), reflecting saturation of clozapine metabolism 2
Abnormal Ratios and Their Significance
Clozapine:norclozapine ratio >2.0 suggests one of two scenarios:
- Non-trough sampling (blood drawn too soon after the last dose) 2
- Saturation of CYP1A2-mediated N-demethylation at higher clozapine concentrations, which occurs naturally at therapeutic levels 2
Markedly elevated ratios (>2.9) may indicate:
- CYP1A2 inhibition from drug interactions (e.g., ciprofloxacin, fluvoxamine) or severe respiratory infections 3, 4
- During a respiratory infection, one case demonstrated a clozapine:norclozapine ratio of 2.9 compared to baseline ratios of 1.0-1.6, associated with a doubling of clozapine levels and toxicity symptoms 3
Important Clinical Caveats
- Norclozapine typically represents 84-91% of the clozapine concentration in most patients at steady state, making it a substantial metabolite 5, 6
- The ratio changes with clozapine concentration due to saturable metabolism—higher clozapine levels naturally produce higher clozapine:norclozapine ratios even without drug interactions 2
- Smoking status significantly affects the ratio because tobacco induces CYP1A2, increasing norclozapine formation; changes in smoking habits require dose adjustment and ratio monitoring 2
- Gender differences exist: nonsmoking women show 40% higher clozapine levels per dose compared to men, which affects the metabolic ratio 6
Monitoring Recommendations
- Measure trough levels on at least two occasions separated by at least one week at a stable dose to establish a reliable baseline ratio 1
- Target therapeutic clozapine levels of 350-550 ng/mL when interpreting the ratio 7, 1
- If the ratio suddenly increases, consider CYP1A2 inhibition from infections or drug interactions and monitor for toxicity signs (sedation, hypotension, tachycardia, myoclonus, seizures) 7, 3