Inflammation-Driven Phenoconversion: How CRP Levels Disrupt CYP2C19-Dependent Voriconazole Metabolism and Redefine Personalized Dosing

Inflammation has a powerful impact on how drugs are processed in the body, especially for patients taking voriconazole, an essential antifungal medication. Voriconazole is a key treatment used to prevent and manage dangerous fungal infections, particularly in people with weakened immune systems, such as those who’ve had hematopoietic stem cell transplants. For these individuals, infections from fungi like Aspergillus can be life-threatening. But one of the biggest challenges with voriconazole is maintaining just the right amount in the bloodstream—enough to fight infection effectively but not so much that it becomes toxic. This balance is hard to achieve because voriconazole has complex pharmacokinetics, meaning its behavior in the body can be quite unpredictable. The way voriconazole is metabolized largely hinges on the enzyme CYP2C19, part of the cytochrome P450 enzyme family, which varies significantly among people due to genetic differences. These differences categorize individuals into various “metabolizer types,” from poor metabolizers (who process the drug slowly) to ultra-rapid metabolizers (who process it quickly). Clinicians generally use a patient’s CYP2C19 genotype as a guide to predict how their body will handle voriconazole and adjust the dose accordingly. However, real-world observations have revealed that this genetic approach doesn’t always match up with actual drug levels in the bloodstream, especially in patients experiencing inflammation. This mismatch can lead to patients either receiving too little of the drug, which limits its effectiveness, or too much, which raises the risk of toxic side effects like liver damage. One major hurdle is that inflammation can disrupt the expected relationship between a person’s CYP2C19 genotype and the enzyme’s activity. When the body is inflamed, it releases certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), that can lower CYP2C19 activity. This phenomenon, known as “phenoconversion,” essentially downgrades a person’s metabolizer type, so even someone genetically predisposed to rapidly metabolize the drug might process it much more slowly under inflammatory conditions. In the case of voriconazole, this slowed metabolism can lead to unusually high drug levels, potentially resulting in toxicity.

This complex situation led researchers, including doctoral candidate Sylvia Klomp, Anette Veringa, Jan-Willem Alffenaar, Mark de Boer, Lambert Span, and Henk-Jan Guchelaar, under the guidance of Professor Jesse Swen from Leiden University Medical Center in the Netherlands, to examine how inflammation affects CYP2C19 activity in patients on voriconazole. Their study, recently published in Clinical and Translational Science, looked specifically at levels of C-reactive protein (CRP), a common marker of inflammation, to see if CRP could be a practical tool for predicting CYP2C19 activity in real-time. The researchers’ goal was to bridge the gap between genotype-based predictions and actual drug metabolism observed in patients dealing with inflammation.  To explore how inflammation impacts drug metabolism, the researchers looked specifically at CRP  levels, a common marker of inflammation, to see how they influence the relationship between a patient’s CYP2C19 genotype and the enzyme activity in those treated with voriconazole. By using data from two clinical trials involving patients on voriconazole for fungal infection prevention or treatment, they were able to assess this connection. Each patient’s CYP2C19 genotype was determined, classifying them as poor, intermediate, normal, rapid, or ultra-rapid metabolizers. In addition to genetic information, the team gathered measurements of each patient’s voriconazole plasma levels and their CRP levels, allowing them to evaluate how the CYP2C19 genotype corresponded with actual voriconazole metabolism under varying inflammatory conditions—a unique approach to unraveling the complexities of drug response in inflamed patients.

The results were quite revealing. Patients with higher CRP levels, signaling notable inflammation, showed voriconazole plasma concentrations that deviated significantly from what would typically be expected based on their genetic profile. For instance, rapid metabolizers, who would generally clear voriconazole quickly, had plasma levels closer to those of intermediate or even poor metabolizers when their CRP levels were elevated. This phenomenon, termed “phenoconversion,” effectively altered patients’ metabolizer status to a slower one, meaning they retained more of the drug in their system than expected. The effect was particularly dramatic in rapid metabolizers, whose voriconazole levels could soar by as much as 486% during inflammation, with normal and intermediate metabolizers seeing increases of 245% and 278%, respectively. This considerable shift in drug levels underscored just how profoundly inflammation can influence voriconazole metabolism, raising concerns about the risk of toxicity if inflammation isn’t factored into dosing decisions. The authors went a step further by conducting a secondary analysis on a smaller subset of patients who had data recorded both when they were in a baseline state and when experiencing inflammation. They found a clear pattern: as CRP levels rose, voriconazole levels followed suit, and as inflammation subsided, drug levels decreased. This consistency suggested that the effects of inflammation on enzyme activity weren’t permanent but could shift back to genotype-predicted metabolism once CRP levels normalized. Additionally, they noted that when inflammation was high (CRP above 50 mg/L), CYP2C19 activity was consistently altered across all metabolizer types, resulting in drug levels that aligned with a slower metabolizer category.

In conclusion, the study by Professor Jesse Swen and his team is significant because it demonstrated how inflammation can dramatically alter drug metabolism, specifically with voriconazole, a critical antifungal medication. Traditionally, personalized medicine relies on genotyping to predict how well a patient will metabolize certain drugs. This study, however, reveals a crucial limitation in that approach: it shows that inflammation can override these genetic predictions, making a patient’s actual drug metabolism unpredictable if inflammatory markers are not also considered. By focusing on CRP levels as an accessible indicator of inflammation, this research suggests a practical way to adjust drug dosing dynamically, based on both genetic and inflammatory factors. We believe the implications for clinical practice are considerable. For patients on voriconazole, especially those at risk of severe fungal infections who may also have fluctuating inflammatory states, this study underscores the need for more nuanced therapeutic drug monitoring. Incorporating CRP measurements into routine practice would allow clinicians to fine-tune voriconazole dosages in real time, enhancing drug safety and efficacy. This approach could also extend to other medications metabolized by the CYP2C19 enzyme, offering a broader impact across treatments where accurate dosing is critical. Furthermore, the study prompts a reevaluation of how we approach pharmacogenetics by integrating real-time biological factors, like inflammation, into patient care—adding a new layer to personalized medicine.