Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations
Marzolini et al.
, Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma..
, Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01177-20
Study of Lopinivar and HCQ plasma concentrations and CRP levels in late stage (treatment initiation median 8 days from onset) COVID-19 patients. The median HCQ plasma concentration was 171 ng/ml, which authors suggest indicates that HCQ levels achieved in vivo
do not result in adequate clinical activity for COVID-19, however this is incorrect as tissue concentration can be many times higher [Ruiz]
Marzolini et al., 8 Jul 2020, peer-reviewed, 18 authors.
Effect of Systemic Inﬂammatory Response to SARS-CoV-2 on
Lopinavir and Hydroxychloroquine Plasma Concentrations
Catia Marzolini,a Felix Stader,a Marcel Stoeckle,a Fabian Franzeck,a,b Adrian Egli,c,d Stefano Bassetti,e Alexa Hollinger,f
Michael Osthoff,e Maja Weisser,a Caroline E. Gebhard,f Veronika Baettig,a Julia Geenen,e Nina Khanna,a
Sarah Tschudin-Sutter,a Daniel Mueller,g Hans H. Hirsch,a,h Manuel Battegay,a Parham Sendia,i
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
Division of Clinical Bacteriology and Mycology, University Hospital Basel, Basel, Switzerland
Applied Microbiology Research, Department of Biomedicine, University of Basel, Basel, Switzerland
Division of Internal Medicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
Intensive Care Unit, University Hospital Basel, Basel, Switzerland
Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
Institute for Infectious Diseases, University of Bern, Bern, Switzerland
Manuel Battegay and Parham Sendi contributed equally to this study.
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 ⫽ 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.
KEYWORDS COVID-19, lopinavir-ritonavir, levels, hydroxychloroquine, inﬂammation
linical trials have been launched to ﬁnd effective treatment against the novel
coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the
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