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.

Abstract

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.

AI evidence extraction

Main findings

In 1106 therapeutic drug monitoring samples, higher AGP and higher CRP levels were associated with higher dose-adjusted clozapine concentrations in a linear mixed effects regression model. The authors report that increasing CRP from 5 to 60 mg/L or AGP from 0.5 to 1.5 g/L would be expected to produce a more than twofold increase in clozapine concentration.

Outcomes measured

• Association between alpha-1-acid glycoprotein (AGP) levels and dose-adjusted clozapine concentrations
• Association between C-reactive protein (CRP) levels and dose-adjusted clozapine concentrations

{
    "study_type": "other",
    "exposure": {
        "band": null,
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": "15-month period (sample collection)"
    },
    "population": "Patients with serum samples sent for routine clozapine therapeutic drug monitoring",
    "sample_size": 1106,
    "outcomes": [
        "Association between alpha-1-acid glycoprotein (AGP) levels and dose-adjusted clozapine concentrations",
        "Association between C-reactive protein (CRP) levels and dose-adjusted clozapine concentrations"
    ],
    "main_findings": "In 1106 therapeutic drug monitoring samples, higher AGP and higher CRP levels were associated with higher dose-adjusted clozapine concentrations in a linear mixed effects regression model. The authors report that increasing CRP from 5 to 60 mg/L or AGP from 0.5 to 1.5 g/L would be expected to produce a more than twofold increase in clozapine concentration.",
    "effect_direction": "unclear",
    "limitations": [],
    "evidence_strength": "insufficient",
    "confidence": 0.7399999999999999911182158029987476766109466552734375,
    "peer_reviewed_likely": "yes",
    "keywords": [
        "clozapine",
        "therapeutic drug monitoring",
        "alpha-1-acid glycoprotein",
        "AGP",
        "C-reactive protein",
        "CRP",
        "acute phase proteins",
        "inflammation",
        "infection",
        "dose-adjusted concentration",
        "linear mixed effects regression"
    ],
    "suggested_hubs": []
}

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