The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions

Abstract

Background and Objective An ever-growing body of evidence supports the impact of cytokine modulation on the patient’s phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug–disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions. Methods We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included. Results Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration–time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration–time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration–time curve between 1.75-fold and 2.56-fold). Conclusions Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01173-8.

Physiologically Based Pharmacokinetic Modeling to Investigate the Disease‐Drug–Drug Interactions between Voriconazole and Nirmatrelvir/Ritonavir in COVID‐19 Patients with CYP2C19 Phenotypes

“…35 Indeed, a growing number of in vitro and clinical studies have shown that several immune mediators, especially IL-6, moderately downregulate the activity of CYP3A4 and weakly-to-moderately downregulate those of CYP2C19. 36,37 In critically ill patients with CAPA, Gatti et al found that Creactive protein and procalcitonin values, inflammatory biomarkers, above defined thresholds could cause voriconazole overexposure, leading to potentially toxic concentrations. 38 In patients with invasive fungal disease, Vreugdenhil et al reported voriconazole C min had a moderate correlation with systemic IL-6 responses, consistent with our prediction (Table S6).…”

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

“…On this basis, implementing a TDM-based expert clinical pharmacological advice program for optimizing voriconazole exposure should become mandatory even in CAPA critically ill patients [ 20 , 31 ], as previously recommended for other settings [ 10 , 32 ]. In this scenario, the careful assessment of the degree of inflammation should be taken into account in the personalization of voriconazole therapy.…”

“…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 ].…”

The combination of CYP2C19 polymorphism and inflammatory cell ratios in prognosis cardiac adverse events after acute coronary syndrome

“…It could be due to the concomitant effect of the CYP2C19 gene polymorphism and inflammatory response on hepatic cytochrome CYP2C19 enzyme activity. A meta-analysis by Milo Gatti and Federico Pea of 26 studies found that an inflammatory response decreased CYP2C19 enzyme activity (as demonstrated by a 1.29–1.97-fold dropping in omeprazole clearance) [ 15 ]. Another study was conducted to investigate the effect of inflammation (via a tablet marker, CRP index) on cytochrome P450 activity in the liver.…”