Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

Lenoir, Camille; Rodieux, Frédérique; Desmeules, Jules Alexandre; Rollason, Victoria; Samer, Caroline Flora

doi:10.1007/s40262-021-01064-4

Cited by 13 publications

(13 citation statements)

References 107 publications

(139 reference statements)

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“…The remaining 537 articles were classified into review articles ( n = 55), in-vitro ( n = 77) or in-silico ( n = 8) studies, and animal ( n = 152) or human ( n = 245) studies. The articles and case reports concerning the pediatric population ( n = 27) are the subject of another systematic review and were excluded from this work ( Lenoir et al, 2021 ). Finally, 218 articles conducted in adults were included and classified into studies ( n = 180) and case reports/series ( n = 38) for analysis ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature

et al. 2021

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Background: Available in-vitro and animal studies indicate that inflammation impacts cytochromes P450 (CYP) activity via multiple and complex transcriptional and post-transcriptional mechanisms, depending on the specific CYP isoforms and the nature of inflammation mediators. It is essential to review the current published data on the impact of inflammation on CYP activities in adults to support drug individualization based on comorbidities and diseases in clinical practice.Methods: This systematic review was conducted in PubMed through 7th January 2021 looking for articles that investigated the consequences of inflammation on CYP activities in adults. Information on the source of inflammation, victim drugs (and CYPs involved), effect of disease-drug interaction, number of subjects, and study design were extracted.Results: The search strategy identified 218 studies and case reports that met our inclusion criteria. These articles were divided into fourteen different sources of inflammation (such as infection, autoimmune diseases, cancer, therapies with immunomodulator…). The impact of inflammation on CYP activities appeared to be isoform-specific and dependent on the nature and severity of the underlying disease causing the inflammation. Some of these drug-disease interactions had a significant influence on drug pharmacokinetic parameters and on clinical management. For example, clozapine levels doubled with signs of toxicity during infections and the concentration ratio between clopidogrel’s active metabolite and clopidogrel is 48-fold lower in critically ill patients. Infection and CYP3A were the most cited perpetrator of inflammation and the most studied CYP, respectively. Moreover, some data suggest that resolution of inflammation results in a return to baseline CYP activities.Conclusion: Convincing evidence shows that inflammation is a major factor to be taken into account in drug development and in clinical practice to avoid any efficacy or safety issues because inflammation modulates CYP activities and thus drug pharmacokinetics. The impact is different depending on the CYP isoform and the inflammatory disease considered. Moreover, resolution of inflammation appears to result in a normalization of CYP activity. However, some results are still equivocal and further investigations are thus needed.

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Section: Resultsmentioning

confidence: 99%

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature

et al. 2021

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“…However, none of these adequately assessed the PK behavior and were consistently excluded from our analysis. Additionally, some of these carried a high risk of bias, as they used only dose-normalized serum concentrations as the main parameter for evaluating differences in drug exposure between pro-inflammatory conditions and baseline [3,[8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical studies carried out both in the adult and in the pediatric settings documented that systemic inflammation may affect the metabolism of several victim drugs. Psychotropic drugs, sedative agents, immunosuppressants, antifungal agents, and antiviral agents were the most investigated victim drugs [3,[8][9][10][11]. Additionally, it has also been postulated that the downregulation of CYP activity caused by systemic inflammation could be reverted by some antiinflammatory biological agents to baseline pre-inflammatory levels [11,12].…”

Section: Key Pointsmentioning

confidence: 99%

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

Gatti

Pea

2022

Clin Pharmacokinet

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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.

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“…During acute or chronic inflammation, released proinflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 act as signaling molecules to elicit marked changes in liver gene expression profiles and lead to the strong downregulation, and activity reduction, of many drug-metabolizing enzymes, including CYP3A4 [ 56 , 57 , 58 , 59 ]. A negative correlation between plasma TNF-α concentrations and midazolam clearance was found in patients with chronic inflammation [ 60 ], and midazolam clearance correlated with plasma levels of the inflammatory marker C-reactive protein in critically ill patients with acute inflammation [ 61 ].…”

Section: Impact Of Inflammation On the Pharmacokinetics Of Midazolammentioning

confidence: 99%

Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

Peter,

Dieudonné,

Zolk

2024

Pharmaceuticals

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Midazolam, a short-acting benzodiazepine, is widely used to alleviate patient anxiety, enhance compliance, and aid in anesthesia. While its side effects are typically dose-dependent and manageable with vigilant perioperative monitoring, serious cardiorespiratory complications, including fatalities and permanent neurological impairment, have been documented. Prolonged exposure to benzodiazepines, such as midazolam, has been associated with neurological changes in infants. Despite attempts to employ therapeutic drug monitoring for optimal sedation dosing, its efficacy has been limited. Consequently, efforts are underway to identify alternative predictive markers to guide individualized dosing and mitigate adverse effects. Understanding these factors is crucial for determining midazolam’s suitability for future administration, particularly after a severe adverse reaction. This article aims to elucidate the factors influencing midazolam’s pharmacokinetics and pharmacodynamics, potentially leading to adverse events. Finally, a case study is presented to exemplify the complex investigation into the causative factors of midazolam-related adverse events.

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Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

Cited by 13 publications

References 107 publications

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature

Influence of Inflammation on Cytochromes P450 Activity in Adults: A Systematic Review of the Literature

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

Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

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