The influence of inflammatory reactions on the serum concentration of clozapine

Elevation of clozapine (CLZ) serum levels due to pharmacokinetic factors can result in a multitude of adverse effects. Whereas the role of drug interactions inhibiting the activity of metabolising enzymes is widely studied, the impact of inflammatory reactions on CLZ biotransformation is not well characterized despite a plethora of literature on inflammation related alterations of drug pharmacokinetics. To examine the question of a potential elevation of CLZ serum levels during inflammatory processes we compared the frequency of an elevated C-reactive-protein (CRP) level as laboratory marker for an inflammatory reaction in patients with a markedly increased CLZ serum level (>800ng/ml; N=27) and patients with a therapeutically recommended CLZ level (350–600ng/ml; N=36). Only cases with CRP determinations in close temporal relation (±1 day) to the CLZ determination were included. We found in patients with elevated CLZ level significantly more often an abnormal CRP value than in patients with normal CLZ level. A binary regression model revealed an elevated CRP value (>1.0mg/dl) as the only relevant predicting factor for an increased CLZ level whereas the variables age, gender, body weight, dosage and smoking did not play a significant role. These results suggest that inflammatory conditions seem to influence the metabolism of CLZ to a considerable degree. As a consequence therapeutic drug monitoring (TDM) during infections is strongly recommended in patients taking CLZ.