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Open Access 01-10-2020 | Pharmacokinetics | Original Research Article

Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

Authors: Pier Giorgio Cojutti, Angela Londero, Paola Della Siega, Filippo Givone, Martina Fabris, Jessica Biasizzo, Carlo Tascini, Federico Pea

Published in: Clinical Pharmacokinetics | Issue 10/2020

Abstract

Background

Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment.

Objective

The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients.

Methods

Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile.

Results

A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (V_d), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16–4.47] vs. 7.24 [5.88–10.38] vs. 9.75 [8.45–13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir.

Conclusions

This is a proof-of-concept of SARS-CoV-2 disease–drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.

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WHO. Coronavirus disease (COVID-19) situation reports. 2020 [cited 30 July 2020]. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. Accessed 31 July 2020.

Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet. 2020;395(10231):1225–8.CrossRefPubMedPubMedCentral

Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020;39(5):405–7.CrossRefPubMedPubMedCentral

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4.CrossRefPubMedPubMedCentral

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):1–11. https://doi.org/10.1001/jamainternmed.2020.0994.CrossRefPubMedCentral

Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends Pharmacol Sci. 2020;41(6):363–82.CrossRefPubMedPubMedCentral

Baldelli S, Corbellino M, Clementi E, Cattaneo D, Gervasoni C. Lopinavir/ritonavir in COVID-19 patients: maybe yes, but at what dose? J Antimicrob Chemother. 2020. https://doi.org/10.1093/jac/dkaa190(Epub 14 May 2020).CrossRefPubMedPubMedCentral

Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol. 2014;54(8):949–57.CrossRefPubMed

Navarro J, Curran A. Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS. HIV AIDS (Auckl). 2016;8:175–82.

10.

Chromsystems Instruments & Chemicals GmbH. MassTox TDM Series A. 2014 [cited 3 Jun 2020]. https://www.chromsystems.com/products/therapeutic-drug-monitoring/masstox-tdm-series-a-anti-hiv-drugs-92924.html. Accessed 31 July 2020.

11.

Cattaneo D, Cattaneo D, Gervasoni C, Corbellino M, Galli M, Riva A, et al. Does lopinavir really inhibit SARS-CoV-2? Pharmacol Res. 2020;158:104898.CrossRefPubMedPubMedCentral

12.

Borges AH, O’Connor JL, Phillips AN, Ronsholt FF, Pett S, Vjecha MJ, et al. Factors associated with plasma IL-6 levels during HIV infection. J Infect Dis. 2015;212(4):585–95.CrossRefPubMedPubMedCentral

13.

Daskapan A, Tran QTD, Cattaneo D, Gervasoni C, Resnati C, Stienstra Y, et al. Darunavir population pharmacokinetic model based on HIV outpatient data. Ther Drug Monit. 2019;41(1):59–65.CrossRefPubMed

14.

Dickinson L, Gurjar R, Stohr W, Bonora S, Owen A, D’Avolio A, et al. Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial. J Antimicrob Chemother. 2020;75(3):628–39.CrossRefPubMed

15.

Renton KW. Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab. 2004;5(3):235–43.CrossRefPubMed

16.

Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006;46:123–49.CrossRefPubMed

17.

Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85(4):434–8.CrossRefPubMed

18.

Evers R, Dallas S, Dickmann LJ, Fahmi OA, Kenny JR, Kraynov E, et al. Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper. Drug Metab Dispos. 2013;41(9):1598–609.CrossRefPubMed

19.

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.CrossRefPubMed

20.

Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome (CRS) in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020;55(5):105954.CrossRefPubMedPubMedCentral

21.

Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020. https://doi.org/10.7326/m20-1550(Epub 12 May 2020).CrossRefPubMedPubMedCentral

22.

Gregoire M, Le Turnier P, Gaborit BJ, Veyrac G, Lecomte R, Boutoille D, et al. Lopinavir pharmacokinetics in COVID-19 patients. J Antimicrob Chemother. 2020. https://doi.org/10.1093/jac/dkaa195(Epub 22 May 2020).CrossRefPubMed

23.

Borku Uysal B, Ikitimur H, Yavuzer S, Ikitimur B, Uysal H, Islamoglu MS, et al. Tocilizumab challenge: a series of cytokine storm therapy experiences in hospitalized Covid-19 pneumonia patients. J Med Virol. 2020. https://doi.org/10.1002/jmv.26111(Epub 2 Jun 2020).CrossRefPubMedPubMedCentral

24.

Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med. 2020;76:43–9.CrossRefPubMedPubMedCentral

25.

Rilinger J, Kern WV, Duerschmied D, Supady A, Bode C, Staudacher DL, et al. A prospective, randomised, double blind placebo-controlled trial to evaluate the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia (TOC-COVID): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):470.CrossRefPubMedPubMedCentral

26.

Machavaram KK, Almond LM, Rostami-Hodjegan A, Gardner I, Jamei M, Tay S, et al. A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6. Clin Pharmacol Ther. 2013;94(2):260–8.CrossRefPubMed

27.

Smith PF, Dodds M, Bentley D, Yeo K, Rayner C. Dosing will be a key success factor in repurposing antivirals for COVID-19. Br J Clin Pharmacol. 2020. https://doi.org/10.1111/bcp.14314(Epub 17 Apr 2020).CrossRefPubMedPubMedCentral

28.

Peck RW, Weiner D, Cook J, Powell JR. A real-world evidence framework for optimising dosing in all patients with COVID-19. Clin Pharmacol Ther. 2020. https://doi.org/10.1002/cpt.1922(Epub 23 May 2020).CrossRefPubMedPubMedCentral

29.

Baker EH, Gnjidic D, Kirkpatrick CMJ, Pirmohamed SM, Wright DFB, Zecharia AY. A call for the appropriate application of clinical pharmacological principles in the search for safe and efficacious COVID-19 (SARS-COV-2) treatments. Br J Clin Pharmacol. 2020. https://doi.org/10.1111/bcp.14416(Epub 8 Jun 2020).CrossRefPubMedPubMedCentral

Title: Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6
Authors: Pier Giorgio Cojutti
Angela Londero
Paola Della Siega
Filippo Givone
Martina Fabris
Jessica Biasizzo
Carlo Tascini
Federico Pea
Publication date: 01-10-2020
Publisher: Springer International Publishing
Keywords: Pharmacokinetics
SARS-CoV-2
Human Immunodeficiency Virus
Published in: Clinical Pharmacokinetics / Issue 10/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-020-00933-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

Abstract

Background

Objective

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusions

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