Florian Simon (1), Marylore Chenel (2), Léa Payen (3), Michel Tod (1)
(1) EA3738, Faculté de médecine de Lyon-Sud, Université de Lyon 1, Oullins, France, (2) Institut de recherches internationales Servier, Direction of clinical PK and pharmacometrics, Suresnes, France, (3) Laboratoire de biochimie-toxicologie, Centre hospitalier Lyon-Sud, Hospices civils de Lyon, Pierre Bénite, France
Objectives:
Systemic inflammation is known to impact drugs pharmacokinetics (PK) by different ways. In vitro tests have shown that exposure to some cytokines, e. g. interleukin(IL)-6, IL-1β or tumor necrosis factor (TNF)α, alters expression and activities of drug-metabolizing enzymes (DME) and drug-transporters in hepatic, intestinal or blood brain barrier (BBB) cell lines [1, 2]. Plasma binding proteins levels are also impacted by inflammatory response, resulting eventually in drug unbound fraction alteration [3]. Clinical studies have highlighted significant differences of PK profiles between patients with high or low systemic inflammation level [4]. These modifications could have clinical consequences and require dosing rate adaptations.
The aim of this work was to build a physiologically-based PK (PBPK) model to predict the impact of inflammation on drug PK. Since CYP3A4, one of the major DME, is strongly impacted by inflammation, midazolam was chosen as a probe for this study.
Methods:
In a previous study, we conducted RNA sequencing and activity tests on intestine and BBB cell lines to to select which DME and ABC transporters are the most impacted by inflammation.
Midazolam PBPK model was built using PK-sim 6.4. The inflammation model was calibrated using midazolam PK profiles after continuous infusion at four levels of CRP (10, 32, 100 and 300 mg/L) in a population of 83 critically ill children [5]. The relationship between CRP concentrations and CYP3A4 metabolic clearance was processed with Mobi 7.4. Metabolic CYP3A4 activity was described as a saturable process following Michaelis-Menten kinetics.
The model was externally validated using visual predictive checks (VPC). The data of 12 rheumatoid arthritis patients taking 0.03 mg/kg midazolam (oral route), before and after administration of sirukumab (an anti-IL-6 monoclonal antibody) [6] were compared to simulations for N = 1000 patients performed with PK-sim for different CRP concentrations (0.5 and 25.3 mg/L).
Results:
Among the different DME expressed in intestinal tissue, the expression and activity of majors CYPs P450 (including CYP3A4) are impaired by exposure to IL-6.
The severity of inflammation, assessed by the CRP level, was related to CYP3A4 metabolic activity by including a factor, kcrp, on the midazolam-metabolite formation rate equation : kcrp = 0.2+0.8*exp(-ln2/25*[CRP])
The VPCs were in good agreement with observations before (CRP = 25.3 mg/L) and after (CRP = 0.5 mg/L) sirukumab administration. Simulated AUCinf and Cmax are also comparable to the observed data.
Conclusions:
These findings suggest that midazolam PK could be predicted depending on the level of CRP. This model may be useful for adapting the dosing rate of CYP3A4 substrates and to avoid toxicities in case of high inflammatory response. This approach will be extended to other substrates of DMEs impacted by inflammatory response and to drugs with high protein binding in plasma (especially with alpha-1-acid glycoprotein). Effect of inflammation on drug-drug interactions will also be studied.
References:
[1] Klein M, Thomas M, Hofmann U, Seehofer D, Damm G, Zanger UM. A Systematic Comparison of the Impact of Inflammatory Signaling on Absorption, Distribution, Metabolism, and Excretion Gene Expression and Activity in Primary Human Hepatocytes and HepaRG Cells. Drug Metabolism and Disposition. 2014;43(2):273-83.
[2] Poller B, Drewe J, Krahenbuhl S, Huwyler J, Gutmann H. Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell Mol Neurobiol. 2010;30(1):63-70.
[3] Mayo PR, Skeith K, Russell AS, Jamali F. Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis. Br J Clin Pharmacol. 2000;50(6):605-13.
[4] Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 2011;89(5):735-40.
[5] Vet NJ, Brussee JM, de Hoog M, Mooij MG, Verlaat CW, Jerchel IS, et al. Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children. Am J Respir Crit Care Med. 2016;194(1):58-66.
[6] Zhuang Y, de Vries DE, Xu Z, Marciniak SJ, Jr., Chen D, Leon F, et al. Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach. J Clin Pharmacol. 2015;55(12):1386-94.
Reference: PAGE 28 (2019) Abstr 9175 [www.page-meeting.org/?abstract=9175]
Poster: Drug/Disease Modelling - Absorption & PBPK