Association Between Levels of the Acute Phase Proteins Alpha‐1‐Acid Glycoprotein and C‐Reactive Protein and Serum Concentrations of Clozapine: A Study of 1106 Therapeutic Drug Monitoring Samples

Several publications have reported elevated clozapine concentrations in patients experiencing infections or inflammatory reactions. Proposed mechanisms include increased levels of pro-inflammatory cytokines that may inhibit clozapine metabolism and enhanced binding of clozapine to the acute phase protein alpha-1-acid glycoprotein (AGP). We collected serum samples sent to our routine laboratory over a 15-month period for the analysis of clozapine. In the 1106 eligible samples, we measured AGP and C-reactive protein (CRP) levels. By using a linear mixed effects regression model, we found a clear association between higher AGP and CRP levels and higher dose-adjusted clozapine concentrations. As an example, an increase in the CRP level from 5 to 60 mg/L or an increase in the AGP level from 0.5 to 1.5 g/L would be expected to cause a more than twofold increase in the clozapine concentration. Our findings support and extend previous case reports and studies, suggesting that increased AGP levels during inflammatory states may play a significant role in the rise of clozapine plasma concentrations observed during illness. We propose that in addition to the clozapine concentration, CRP levels and clinical signs of adverse effects and toxicity should be closely monitored in patients with infectious or inflammatory diseases.