A puzzling case of increased serum clozapine levels in a patient with inflammation and infection.

A 23-year old male with a history of schizophrenia treated with clozapine 900 mg/d was admitted to the hospital for a gastrointestinal infection. The trough serum concentration of clozapine at admission was 9074 nmole/L, that is, almost 4-fold the upper limit of the reference range. The patients did not report any adverse effects of clozapine. The clozapine concentration 1 month earlier had been 1919 nmole/L, which is well within the reference range. There seems to be 2 different mechanisms explaining the increase in clozapine levels in this patient. First, a downregulation of CYP enzyme activities, which primarily seems to be mediated by interleukin-6, takes place during infection and inflammation. Second, the concentration of the acute phase protein α1-acid glycoprotein (AGP; orosomucoid) increases during infection and inflammation. As approximately 95% of clozapine is bound to AGP, the concentration of clozapine will increase in parallel with the increase in AGP. A therapeutic drug monitoring analysis measures the total drug concentration (ie, the concentration of unbound plus plasma protein bound drug), whereas the concentration of free drug exerts its pharmacological effects. Thus, this second mechanism will, in contrast to the first mechanism, not affect the clinical effect of clozapine. Although the patient was also treated with ciprofloxacin, which has been reported to inhibit the metabolism of clozapine, the clozapine levels did not further increase. This case illustrates the complex interrelationship between serum levels of clozapine and an intercurrent infection treated with potentially interacting antibiotics.