Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Catia Marzolini, Felix Stader, Marcel Stoeckle, Fabian Franzeck, Adrian Egli, Stefano Bassetti, Alexa Hollinger, Michael Osthoff, Maja Weisser, Caroline E Gebhard, Veronika Baettig, Julia Geenen, Nina Khanna, Sarah Tschudin-Sutter, Daniel Mueller, Hans H Hirsch, Manuel Battegay, Parham Sendi
Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 g/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r ϭ 0.37, P Ͻ 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC 50 ) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.
References
Baldelli, Corbellino, Clementi, Cattaneo, Gervasoni, Lopinavir/ritonavir in COVID-19 patients: maybe yes, but at what dose?, J Antimicrob Chemother,
doi:10.1093/jac/dkaa190Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2016638Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2001282Choy, Wong, Kaewpreedee, Sia, Chen et al., Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro, Antiviral Res,
doi:10.1016/j.antiviral.2020.104786Dickmann, Patel, Rock, Wienkers, Slatter, Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drugmetabolizing enzymes in human hepatocyte culture, Drug Metab Dispos,
doi:10.1124/dmd.111.038679Dumond, Rigdon, Mollan, Tierney, Kashuba et al., Brief report: significant decreases in both total and unbound lopinavir and amprenavir exposures during coadministration: ACTG Protocol A5143/A5147s results, J Acquir Immune Defic Syndr,
doi:10.1097/QAI.0000000000000777Eichbaum, Blank, Burhenne, Mikus, Concentration effect relationship of CYP3A inhibition by ritonavir in humans, Eur J Clin Pharmacol,
doi:10.1007/s00228-013-1530-8Eron, Feinberg, Kessler, Horowitz, Witt et al., Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial, J Infect Dis,
doi:10.1086/380799Fajgenbaum, Khor, Gorzewski, Tamakloe, Powers et al., Treatments administered to the first 9152 reported cases of COVID-19: a systematic review, Infect Dis Ther,
doi:10.1007/s40121-020-00303-8Fan, Zhang, Liu, Yang, Zheng et al., Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients, Clin Infect Dis,
doi:10.1093/cid/ciaa623Ford, Vitoria, Rangaraj, Norris, Calmy et al., Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID-19: initial assessment, J Int AIDS Soc,
doi:10.1002/jia2.25489Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2012410Gregoire, Turnier, Gaborit, Veyrac, Lecomte et al., Lopinavir pharmacokinetics in COVID-19 patients, J Antimicrob Chemother,
doi:10.1093/jac/dkaa195Hefner, Shams, Unterecker, Falter, Hiemke, Inflammation and psychotropic drugs: the relationship between C-reactive protein and antipsychotic drug levels, Psychopharmacology,
doi:10.1007/s00213-015-3976-0Kojima, Yabe, Kaneko, Hirano, Ishikawa et al., Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis, Mod Rheumatol,
doi:10.1007/s10165-012-0782-yLe, Li, Yuan, Shord, Nie et al., FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or lifethreatening cytokine release syndrome, Oncologist,
doi:10.1634/theoncologist.2018-0028Lee, Glaeser, Smith, Roberts, Moeckel et al., Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry, J Biol Chem,
doi:10.1074/jbc.M411092200Markanday, Acute phase reactants in infections: evidence-based review and a guide for clinicians, Open Forum Infect Dis,
doi:10.1093/ofid/ofv098Martin-Blondel, Ruiz, Murris, Faguer, Duhalde et al., Hydroxychloroquine in COVID-19 patients: what still needs to be known about the kinetics, Clin Infect Dis,
doi:10.1093/cid/ciaa558Morgan, Goralski, Piquette-Miller, Renton, Robertson et al., Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer, Drug Metab Dispos,
doi:10.1124/dmd.107.018747Morgan, Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics, Clin Pharmacol Ther,
doi:10.1038/clpt.2008.302Morita, Takahashi, Yoshida, Yokota, Population pharmacokinetics of hydroxychloroquine in Japanese patients with cutaneous or systemic lupus erythematosus, Ther Drug Monit,
doi:10.1097/FTD.0000000000000261Mueck, Kubitza, Becka, Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects, Br J Clin Pharmacol,
doi:10.1111/bcp.12075Nijland, Homme, Rongen, Van Uden, Van Crevel et al., High incidence of adverse events in healthy volunteers receiving rifampicin and adjusted doses of lopinavir/ritonavir tablets, AIDS,
doi:10.1097/QAD.0b013e3282faa71eOfotokun, Chuck, Binongo, Palau, Lennox et al., Lopinavir/ritonavir pharmacokinetic profile: impact of sex and other covariates following a change from twice-daily to once-daily therapy, J Clin Pharmacol,
doi:10.1177/0091270007302564Renton, Regulation of drug metabolism and disposition during inflammation and infection, Expert Opin Drug Metab Toxicol,
doi:10.1517/17425255.1.4.629Schoergenhofer, Jilma, Stimpfl, Karolyi, Zoufaly, Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19), Ann Intern Med,
doi:10.7326/m20-1550Sheahan, Sims, Leist, Schäfer, Won et al., Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV, Nat Commun,
doi:10.1038/s41467-019-13940-6Stader, Khoo, Stoeckle, Back, Hirsch et al., Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interaction effect, J Antmicrob Chemother,
doi:10.1093/jac/dkaa253Stader, Kinvig, Penny, Battegay, Siccardi et al., Physiologically based pharmacokinetic modelling to identify pharmacokinetic parameters driving drug exposure changes in the elderly, Clin Pharmacokinet,
doi:10.1007/s40262-019-00822-9Testa, Prandoni, Paoletti, Morandini, Tala et al., Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience, J Thromb Haemost,
doi:10.1111/jth.14871Tripathy, Dassarma, Roy, Chabalala, Matsabisa, A review on possible modes of actions of chloroquine/hydroxychloroquine: repurposing against SAR-COV-2 (COVID 19) pandemic, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106028Vreugdenhil, Van Der Velden, Feuth, Kox, Pickkers et al., Moderate correlation between systemic IL-6 responses and CRP with trough concentrations of voriconazole, Br J Clin Pharmacol,
doi:10.1111/bcp.13627Who, Solidarity" clinical trial for COVID-19 treatments
Wu, Mcgoogan, Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention, JAMA,
doi:10.1001/jama.2020.2648Xu, Zhu, Chan, Lu, Shen et al., Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2, J Pharm Sci,
doi:10.1002/jps.24663Zhang, Li, Shen, Chen, Qi, Rational use of tocilizumab in the treatment of novel coronavirus pneumonia, Clin Drug Invest,
doi:10.1007/s40261-020-00917-3Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved ␣-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405
