Toxic clozapine level as first indication of severe, acute infection

BACKGROUND: Clozapine levels can be influenced by many factors, including pharmacogenomic variability, pharmacokinetic drug interactions, and infection/inflammation. The concentration-to-dose ratio (C/D), a measure of a medication's rate of metabolism and clearance, may increase during an acute infection due to decreased medication metabolism and clearance. CASE REPORT: A 56-year-old White man was restarted on clozapine and titrated up to 350 mg/d with therapeutic steady-state levels (C/D 1.11) on hospital day (HD) 69. At this time, he was also being treated for COPD exacerbation. For the next month, he continued to complain of cough, but vital signs and chest x-ray remained normal. Labs were unremarkable except for occasional leukocytosis that would resolve on repeat evaluation. A routine clozapine level drawn on HD 104, resulted on day 108 and showed clozapine toxicity with C/D 4.05, although the patient was asymptomatic. After receipt of labs on day 109, showing elevated WBC count, he was immediately sent to the emergency room where he was admitted for treatment of pneumonia. On return to the state hospital, the patient was continued on 100 mg clozapine and titrated to 200 mg/d based on low drug levels. He continued to do well on 200 mg/d clozapine with C/D averaging 1.13 (range, 0.75-1.52). DISCUSSION: Acute infection and illness can lead to significantly increased clozapine levels and toxicity, even if symptoms of toxicity are minimal or absent. This appears to be the first report of a toxic level being the first indication of severe medical illness.