Effects of inflammation on voriconazole levels: A systematic review

Abstract

Aims This study aimed to review the studies evaluating the effect of the inflammatory state on voriconazole (VRZ) levels. Methods The study included randomized clinical trials, cohort studies, and case–control studies that focused on the influence of the inflammatory state on VRZ levels. Following the preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guidelines, relevant articles published until 2021 were searched in several databases, including PubMed, Embase, Web of Science and the Cochrane Library. Results Twenty studies were included in this review, of which 15 described adult populations, three described paediatric populations, and two included both adult and paediatric populations. Seventeen studies used C‐reactive protein (CRP) as an indicator of inflammation, six described a dose–response relationship for the effect of inflammation represented by CRP on VRZ concentrations, and four examined the effect of CRP on the metabolic rate of VRZ. Conclusions Our findings showed that the level of inflammation can significantly affect VRZ levels. However, the effect of inflammation on VRZ concentrations in children is controversial and must be analysed along with age. Clinicians dosing VRZ should take into account the patient's inflammatory state. The impact of inflammation on genotype‐based dosing decisions requires further study to explain the high pharmacokinetic variability of VRZ.

Impact of Inflammation on Voriconazole Exposure in Critically ill Patients Affected by Probable COVID-19-Associated Pulmonary Aspergillosis

“…Several factors may be responsible for the large inter-and intra-individu in voriconazole Cmin commonly retrieved during treatment with standard regimens [18]. Specifically, voriconazole pharmacokinetics may be strongly genetic polymorphisms of CYP2C19 isoenzyme, by drug-drug interactions w 2C19, or 3A4 modulators, and/or by the inflammatory status [14,18,23,24]. In Figure 2.…”

“…Several factors may be responsible for the large inter- and intra-individual variability in voriconazole C min commonly retrieved during treatment with standard fixed dosing regimens [ 18 ]. Specifically, voriconazole pharmacokinetics may be strongly affected by genetic polymorphisms of CYP2C19 isoenzyme, by drug–drug interactions with CYP2C9, 2C19, or 3A4 modulators, and/or by the inflammatory status [ 14 , 18 , 23 , 24 ]. In regard to the latter, several real-world studies carried out, mainly in patients with hematological malignancies undergoing hematopoietic stem cell/bone marrow transplantation and/or in solid organ transplant recipients, showed in the last decade that thresholds of inflammatory biomarkers like CRP or PCT may be significantly associated with toxic voriconazole levels [ 14 ].…”

“…Specifically, voriconazole pharmacokinetics may be strongly affected by genetic polymorphisms of CYP2C19 isoenzyme, by drug–drug interactions with CYP2C9, 2C19, or 3A4 modulators, and/or by the inflammatory status [ 14 , 18 , 23 , 24 ]. In regard to the latter, several real-world studies carried out, mainly in patients with hematological malignancies undergoing hematopoietic stem cell/bone marrow transplantation and/or in solid organ transplant recipients, showed in the last decade that thresholds of inflammatory biomarkers like CRP or PCT may be significantly associated with toxic voriconazole levels [ 14 ]. Dote et al [ 25 ] found in a cohort of 63 mixed patients (mainly hematological) that CRP values > 4.7 mg/dL were associated with an increased risk of voriconazole C min exceeding 4 mg/L.…”

“…Among the different factors possibly impacting on voriconazole exposure, recent evidence found that the degree of inflammation may significantly affect voriconazole concentrations [ 14 , 15 , 16 , 17 ]. Voriconazole metabolism is mediated by CYP2C9, CYP2C19, and CYP3A4 [ 18 ].…”

“…Indeed, an ever-growing number of studies showed that several pro-inflammatory cytokines, especially IL-6, may moderately downregulate the activity of CYP3A4 and weakly-to-moderately downregulate those of CYP2C9 and CYP2C19 [ 19 , 20 ]. Considering that inflammation represents a common feature that shows remarkable proportion among ICU patients, a relevant impact on the occurrence of voriconazole overexposure and toxicity could not be ruled out [ 14 ]. However, no studies investigated this issue in the challenging scenario of CAPA.…”