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Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations.
Antimicrob Agents Chemother. 2020 08 20; 64(9)AA

Abstract

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 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 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 (EC50) 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.

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Authors+Show Affiliations

Marzolini C
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland catia.marzolini@usb.ch parham.sendi@usb.ch.
Stader F
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Stoeckle M
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Franzeck F
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland. Research and Analysis Services, University Hospital Basel and University of Basel, Basel, Switzerland.
Egli A
Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland. Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland.
Bassetti S
Division of Internal Medicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
Hollinger A
Intensive Care Unit, University Hospital Basel, Basel, Switzerland.
Osthoff M
Division of Internal Medicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
Weisser M
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Gebhard CE
Intensive Care Unit, University Hospital Basel, Basel, Switzerland.
Baettig V
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Geenen J
Division of Internal Medicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
Khanna N
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Tschudin-Sutter S
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Mueller D
Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
Hirsch HH
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland. Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Battegay M
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland.
Sendi P
Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and University of Basel, Basel, Switzerland catia.marzolini@usb.ch parham.sendi@usb.ch. Institute for Infectious Diseases, University of Bern, Bern, Switzerland.

MeSH

AdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntiviral AgentsBetacoronavirusBiomarkersC-Reactive ProteinCOVID-19Coronavirus InfectionsCytokine Release SyndromeDrug Administration ScheduleDrug CombinationsFemaleHospitals, UniversityHumansHydroxychloroquineLength of StayLopinavirMaleMiddle AgedPandemicsPneumonia, ViralRetrospective StudiesRitonavirSARS-CoV-2Severity of Illness IndexSurvival Analysis

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32641296

Citation

Marzolini, Catia, et al. "Effect of Systemic Inflammatory Response to SARS-CoV-2 On Lopinavir and Hydroxychloroquine Plasma Concentrations." Antimicrobial Agents and Chemotherapy, vol. 64, no. 9, 2020.
Marzolini C, Stader F, Stoeckle M, et al. Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations. Antimicrob Agents Chemother. 2020;64(9).
Marzolini, C., Stader, F., Stoeckle, M., Franzeck, F., Egli, A., Bassetti, S., Hollinger, A., Osthoff, M., Weisser, M., Gebhard, C. E., Baettig, V., Geenen, J., Khanna, N., Tschudin-Sutter, S., Mueller, D., Hirsch, H. H., Battegay, M., & Sendi, P. (2020). Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations. Antimicrobial Agents and Chemotherapy, 64(9). https://doi.org/10.1128/AAC.01177-20
Marzolini C, et al. Effect of Systemic Inflammatory Response to SARS-CoV-2 On Lopinavir and Hydroxychloroquine Plasma Concentrations. Antimicrob Agents Chemother. 2020 08 20;64(9) PubMed PMID: 32641296.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations. AU - Marzolini,Catia, AU - Stader,Felix, AU - Stoeckle,Marcel, AU - Franzeck,Fabian, AU - Egli,Adrian, AU - Bassetti,Stefano, AU - Hollinger,Alexa, AU - Osthoff,Michael, AU - Weisser,Maja, AU - Gebhard,Caroline E, AU - Baettig,Veronika, AU - Geenen,Julia, AU - Khanna,Nina, AU - Tschudin-Sutter,Sarah, AU - Mueller,Daniel, AU - Hirsch,Hans H, AU - Battegay,Manuel, AU - Sendi,Parham, Y1 - 2020/08/20/ PY - 2020/06/09/received PY - 2020/07/06/accepted PY - 2020/7/10/pubmed PY - 2020/9/4/medline PY - 2020/7/10/entrez KW - COVID-19 KW - hydroxychloroquine KW - inflammation KW - levels KW - lopinavir-ritonavir JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 64 IS - 9 N2 - 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 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 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 (EC50) 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/32641296/Effect_of_Systemic_Inflammatory_Response_to_SARS_CoV_2_on_Lopinavir_and_Hydroxychloroquine_Plasma_Concentrations_ DB - PRIME DP - Unbound Medicine ER -