PMID- 32641296
OWN - NLM
STAT- MEDLINE
DCOM- 20200902
LR  - 20201218
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 64
IP  - 9
DP  - 2020 Aug 20
TI  - Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and 
      Hydroxychloroquine Plasma Concentrations.
LID - 10.1128/AAC.01177-20 [doi]
LID - e01177-20
AB  - 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 mug/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 (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.
CI  - Copyright (c) 2020 American Society for Microbiology.
FAU - Marzolini, Catia
AU  - Marzolini C
AUID- ORCID: 0000-0002-2312-7050
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland catia.marzolini@usb.ch 
      parham.sendi@usb.ch.
FAU - Stader, Felix
AU  - Stader F
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Stoeckle, Marcel
AU  - Stoeckle M
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Franzeck, Fabian
AU  - Franzeck F
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
AD  - Research and Analysis Services, University Hospital Basel and University of 
      Basel, Basel, Switzerland.
FAU - Egli, Adrian
AU  - Egli A
AD  - Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, 
      Switzerland.
AD  - Applied Microbiology Research, Department of Biomedicine, University of Basel, 
      Basel, Switzerland.
FAU - Bassetti, Stefano
AU  - Bassetti S
AD  - Division of Internal Medicine and Department of Clinical Research, University 
      Hospital Basel and University of Basel, Basel, Switzerland.
FAU - Hollinger, Alexa
AU  - Hollinger A
AD  - Intensive Care Unit, University Hospital Basel, Basel, Switzerland.
FAU - Osthoff, Michael
AU  - Osthoff M
AD  - Division of Internal Medicine and Department of Clinical Research, University 
      Hospital Basel and University of Basel, Basel, Switzerland.
FAU - Weisser, Maja
AU  - Weisser M
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Gebhard, Caroline E
AU  - Gebhard CE
AD  - Intensive Care Unit, University Hospital Basel, Basel, Switzerland.
FAU - Baettig, Veronika
AU  - Baettig V
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Geenen, Julia
AU  - Geenen J
AD  - Division of Internal Medicine and Department of Clinical Research, University 
      Hospital Basel and University of Basel, Basel, Switzerland.
FAU - Khanna, Nina
AU  - Khanna N
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Tschudin-Sutter, Sarah
AU  - Tschudin-Sutter S
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Mueller, Daniel
AU  - Mueller D
AD  - Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
FAU - Hirsch, Hans H
AU  - Hirsch HH
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
AD  - Transplantation & Clinical Virology, Department of Biomedicine, University of 
      Basel, Basel, Switzerland.
FAU - Battegay, Manuel
AU  - Battegay M
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland.
FAU - Sendi, Parham
AU  - Sendi P
AD  - Division of Infectious Diseases & Hospital Hygiene, University Hospital Basel and 
      University of Basel, Basel, Switzerland catia.marzolini@usb.ch 
      parham.sendi@usb.ch.
AD  - Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200820
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antiviral Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Drug Combinations)
RN  - 0 (lopinavir-ritonavir drug combination)
RN  - 2494G1JF75 (Lopinavir)
RN  - 4QWG6N8QKH (Hydroxychloroquine)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - I031V2H011 (tocilizumab)
RN  - O3J8G9O825 (Ritonavir)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/therapeutic use
MH  - Antiviral Agents/blood/*pharmacokinetics/pharmacology
MH  - Betacoronavirus/*drug effects/immunology/pathogenicity
MH  - Biomarkers/blood
MH  - C-Reactive Protein/metabolism
MH  - COVID-19
MH  - Coronavirus Infections/*drug therapy/immunology/mortality/virology
MH  - Cytokine Release Syndrome/*drug therapy/immunology/mortality/virology
MH  - Drug Administration Schedule
MH  - Drug Combinations
MH  - Female
MH  - Hospitals, University
MH  - Humans
MH  - Hydroxychloroquine/blood/*pharmacokinetics/pharmacology
MH  - Length of Stay/statistics & numerical data
MH  - Lopinavir/blood/*pharmacokinetics/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Pandemics
MH  - Pneumonia, Viral/*drug therapy/immunology/mortality/virology
MH  - Retrospective Studies
MH  - Ritonavir/blood/*pharmacokinetics/pharmacology
MH  - SARS-CoV-2
MH  - Severity of Illness Index
MH  - Survival Analysis
PMC - PMC7449226
OTO - NOTNLM
OT  - COVID-19
OT  - hydroxychloroquine
OT  - inflammation
OT  - levels
OT  - lopinavir-ritonavir
EDAT- 2020/07/10 06:00
MHDA- 2020/09/04 06:00
PMCR- 2020/08/20
CRDT- 2020/07/10 06:00
PHST- 2020/06/09 00:00 [received]
PHST- 2020/07/06 00:00 [accepted]
PHST- 2020/07/10 06:00 [pubmed]
PHST- 2020/09/04 06:00 [medline]
PHST- 2020/07/10 06:00 [entrez]
PHST- 2020/08/20 00:00 [pmc-release]
AID - AAC.01177-20 [pii]
AID - 01177-20 [pii]
AID - 10.1128/AAC.01177-20 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2020 Aug 20;64(9):e01177-20. doi: 
      10.1128/AAC.01177-20. Print 2020 Aug 20.