 This month we publish a contribution to the March Compass concerning the impact of severe inflammation on drug concentrations and Therapeutic Drug Monitoring, specifically in the context of Voriconazole metabolism. Anette Veringa and Jan-Willem Alffenaar present their work, writing on behalf of the Anti-Infective Drug Committee. Their findings have implications for any drug metabolized by CYP450 iso-enzymes, and highlights the importance of knowledge of patient genotypes. Drugs with extensive protein binding exhibit a further layer of complexity in managing these patients.
Anette Veringa (left) Jan-Willem C. Alffenaar (right)
During inflammation, several drug-metabolizing enzymes, including cytochrome P450 iso-enzymes, are down-regulated (1,2). Since voriconazole is mainly metabolized by cytochrome P450 (CYP) iso-enzymes (3), the metabolism of this drug can be influenced during inflammation. In two retrospective studies, a higher voriconazole trough concentration was observed during severe inflammation (4,5). In another retrospective study including both voriconazole and voriconazole-N-oxide concentrations a reduced voriconazole metabolism was observed during inflammation (6). Recently we performed a prospective study, with repeated measurements of voriconazole and voriconazole-N-oxide to assess the effect of inflammation on the metabolic ratio of voriconazole over time. The degree of inflammation was determined using C-reactive protein (CRP) concentrations. In this prospective study, we showed that during severe inflammation the metabolism of voriconazole was reduced and high and potentially toxic voriconazole concentrations were observed, while the metabolic ratio increased and trough concentrations decreased significantly if the infection subsided, reflected by decreasing CRP concentrations (7). The effect of inflammation was even more pronounced depending on the CYP2C19 genotype of the patient. For instance, for intermediate metabolizers of CYP2C19, the metabolism of voriconazole is further reduced compared with extensive and ultra-rapid metabolizers (7). The effect of inflammation on CYP2C19 poor metabolizers (PMs) could not be studied since we found no PMs amongst our Caucasian patients (8). It is questionable if inflammation has an additional inhibitory effect on voriconazole metabolism in PMs, since these individuals carry two non-functioning alleles (9). Besides CYP2C19, voriconazole is also metabolized by CYP2C9 and CYP3A4, though to a lesser extent (3). The metabolic capacity of CYP2C9 and CYP3A4 can also be reduced during inflammation (10,11). In our study, solely CYP2C19 genotyping was performed. However, a reduced metabolic capacity for CYP2C9 is commonly observed in the Caucasian population (12). For instance, an even larger effect may be observed during inflammation in intermediate metabolizers of both CYP2C19 and CYP2C9. In a recent study involving 29 patients it was shown that a genetic score, including both CYP2C19 and CYP3A4 genotype and inflammation, significantly influenced observed voriconazole trough concentrations (13). A genetic score including all CYP450 genotypes of interest would provide better information on the metabolic capacity of the liver and the effect of inflammation on vorionazole metabolism. Here, the main metabolite of a drug, active or not, gives important additional information on drug metabolism (14). In children, the effect of inflammation on voriconazole trough concentration is less pronounced compared to adults. In a retrospective study, we showed that in children aged > 12 years, voriconazole trough concentrations are higher at elevated CRP concentrations (> 150 mg/L). However, in children aged < 12 years, a trend of increased voriconazole concentrations at a higher degree of inflammation was not observed (15). This could be explained by a higher clearance of voriconazole observed in children aged < 12 years. Yanni and colleagues showed that CYP2C19 activity was higher in children aged < 12 years compared with adults, as well as flavin-containing mono-oxygenase (FMO) activity (16). Although both CYP2C19 and FMO activity is reduced during inflammation (2), this does not seem to influence the metabolic capacity of the liver. For other drugs, including theophylline and midazolam, a reduced clearance was shown in children aged < 12 years during inflammation (17,18). However, these drugs are primarily metabolised by CYP1A2 and CYP3A4, which could explain the difference in drug clearance during inflammation. In summary, in the retrospective analysis we performed voriconazole trough concentrations seem not increased during severe inflammation in children aged < 12 years. For children aged > 12 years higher voriconazole concentrations were observed at CRP concentrations > 150 mg/L. This can result in potentially toxic drug concentrations in these children. Since our study consisted of retrospective data and a small number of included patients, our findings should be confirmed by repeated measurements of voriconazole and voriconazole-N-oxide concentrations determined prospectively. The synthesis of CRP is mainly regulated by the cytokine interleukin-6 (IL-6) (9). IL-6 concentrations may serve as an early predictor of inflammation resulting in decreased metabolism of voriconazole and hence higher trough concentrations. It would therefore be of interest to perform a future study investigating IL-6 concentrations with voriconazole concentrations over time. The effect of inflammation should be studied for other drugs metabolized primarily by CYP450 iso-enzymes and with a small therapeutic range; during severe inflammation, a genotypic extensive metabolizer can become a phenotypic poor metabolizer (19). This can result in potentially toxic drug concentrations. A distinction should be made for drugs that are highly protein bound, including those bound to albumin or α1-acid glycoprotein. While the plasma concentration of albumin decreases during inflammation, α1-acid glycoprotein plasma concentrations increase (20). During inflammation, higher total concentrations can be observed for a drug metabolized via CYP450 iso-enzymes. However, if the drug is mainly bound to α1-acid glycoprotein, free-drug concentration may be unchanged due to an increased α1-acid glycoprotein plasma concentration and subsequently an increased protein binding of the drug. In contrast, for drugs highly bound to albumin a lower total concentration of a drug may be observed, while the free concentration may be unchanged (21). In summary, inflammation seems to be an important factor influencing voriconazole metabolism in adults and possibly also in children aged 12 years or older. Therefore, inflammatory parameters like CRP concentrations should be measured routinely for these patients during treatment with voriconazole to better understand variable voriconazole concentrations. In addition, for other drugs primarily metabolized by CYP450 iso-enzymes, inflammation can significantly contribute to variable plasma concentrations. References (1) Morgan ET. Clin Pharmacol Ther 2009 Apr;85(4):434-438.
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