Clozapine toxicity: A discussion of pharmacokinetic factors

This report seeks to analyze and discuss different pharmacokinetic factors that might be responsible for a case of clozapine toxicity on a conventional clozapine dose. A 41-year-old Caucasian male with schizoaffective disorder was cross-titrated to 400mg/day of clozapine to manage inadequate response on 6mg/day of risperidone. A week later the patient became gradually confused and disoriented and eventually lost consciousness. The combined clozapine and norclozapine levels were elevated at 2500ng/mL. Patient's symptoms resolved after clozapine was reduced to 75mg/day with a reduction in clozapine and norclozapine levels to 420ng/mL. Toxic clozapine levels may result from abnormal drug absorption, distribution, metabolism or elimination. Changes in absorption and/or distribution are unlikely to explain the toxic levels as clozapine has relatively high oral bioavailability at steady state and a large volume of distribution. In terms of metabolism, clozapine is primarily metabolized by CYP1A2, which biotransforms clozapine to norclozapine. However, it is unlikely that CYP1A2 was responsible, as any reduction in CYP1A2 activity would have likely altered clozapine and norclozapine ratio, which was not observed in this patient. Involvement of other CYP enzymes in the development of clozapine toxicity was ruled out through genotyping. Since liver and renal function tests were also within normal limit, it is difficult to pinpoint a single pharmacokinetic factor responsible for unusually high clozapine and norclozapine levels in this patient. However, a combination of various pharmacokinetic factors may provide an explanation for clozapine toxicity in this patient.

Conclusion: Some patients can develop unusually high levels of clozapine and/or its metabolites on routine clozapine dosages resulting in clinically serious adverse effects as observed in our patient.