Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates

Simon, Florian; Gautier-Veyret, Élodie; Truffot, Aurélie; Chenel, Marylore; Payen, Léa; Stanke‐Labesque, Françoise; Tod, Michel

doi:10.1007/s11095-021-03019-7

Cited by 29 publications

(27 citation statements)

References 40 publications

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“…While IL-6 appears to be the key element in modulating CYP activities during inflammation, a recent study developed a model that predicted the impact of systemic CRP levels on CYP3A4 and CYP2C19 activities (Simon et al, 2021). Optimal drug use leads to takes into account the contribution of covariates to predict the dose needed to achieve a target concentration and thus reduce the inter-and intra-individual variability in drug response (Darwich et al, 2021).…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

“…Inflammatory disease is an example of a special population and numerous PBPK models have been developed and validated to predict IL-6 mediated drug-disease ( Machavaram et al, 2013 ; Xu et al, 2015 ; Jiang et al, 2016 ; Radke et al, 2017 ; Xu et al, 2018 ; Machavaram et al, 2019 ). While IL-6 appears to be the key element in modulating CYP activities during inflammation, a recent study developed a model that predicted the impact of systemic CRP levels on CYP3A4 and CYP2C19 activities ( Simon et al, 2021 ). Optimal drug use leads to takes into account the contribution of covariates to predict the dose needed to achieve a target concentration and thus reduce the inter- and intra-individual variability in drug response ( Darwich et al, 2021 ).…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

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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: Discussion and Perspectivesmentioning

confidence: 99%

Section: Discussion and Perspectivesmentioning

confidence: 99%

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

et al. 2021

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“…There are some aspects in the application of DEX for the treatment of COVID-19 that should be considered when analysing the data from this study. Firstly, severe COVID-19 is associated with a systemic hyper-inflammation state with increased cytokine levels and highly elevated C-reactive protein (CRP) all of which are known to impact drug PK through the downregulation of CYP isoenzymes (Dickmann et al, 2011;Simon et al, 2019;Simon et al, 2021). The current PBPK model does not incorporate these mechanisms due to limited data/ability to verify the model.…”

Section: Discussionmentioning

confidence: 99%

PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease

et al. 2022

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The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18–60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%–60%) and the plasma concentrations increased (170%–400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

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“…Therefore, renal impairment was not included in our estimations. However, other factors such as concomitant intake of CYP3A inhibitors or inducers or inflammation might impact the PK of olaparib [ 26 , 27 ]. The use of a physiologically-based PK (PBPK) model could be more accurate to predict C minPred in such patients.…”

Section: Discussionmentioning

confidence: 99%

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

et al. 2021

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Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

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Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates

Cited by 29 publications

References 40 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

PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

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