key: cord-0990820-tsqc9u3z
authors: Schoergenhofer, Christian; Jilma, Bernd; Stimpfl, Thomas; Karolyi, Mario; Zoufaly, Alexander
title: Pharmacokinetics of Lopinavir and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19)
date: 2020-05-12
journal: Ann Intern Med
DOI: 10.7326/m20-1550
sha: 3a5364e4465fe5bf7e506fee801213556638dd1a
doc_id: 990820
cord_uid: tsqc9u3z

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because they provide more robust pharmacokinetic information for single time-point assessments and were frequently investigated in HIV trials, which makes the data comparable.

Trough concentrations of lopinavir ranged from 6.2 to 24.3 μg/mL (median, 13.6 μg/mL) (Table) . Interestingly, in this small sample, trough concentrations seemed to be associated with C-reactive protein (Spearman correlation coefficient r S = 0.81). All patients had an unremarkable disease course and were discharged from the normal care ward. Specific adverse effects of lopinavir and ritonavir were not observed.

Discussion: We report the first pharmacokinetic data of lopinavir and ritonavir in patients hospitalized with COVID-19. Lopinavir trough levels were approximately 2-fold higher in our population than in patients with HIV receiving the same dose (7.1 μg/mL) (1). This may have been caused by inflammation-induced downregulation of cytochrome P450 enzyme activity and reduced drug metabolism, which is mediated by proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-␣ (4). The observed correlation of drug concentrations with C-reactive protein, a downstream marker of IL-6, supports this hypothesis and is notable because C-reactive protein levels were not exceedingly high in our population. High levels of IL-6 are associated with disease severity (5) , and IL-6 -blocking therapies are being investigated in several clinical trials. Thus, drug metabolism may be even more impaired in more severe cases of COVID-19. Furthermore, clinicians should be aware that antiinflammatory treatments may severely affect the pharmacokinetics of cytochrome enzyme-dependent drugs.

This analysis has limitations. Only trough levels were quantified, and more detailed pharmacokinetics were not available. Also, there are no data on the half-maximal effective dose of lopinavir for SARS-CoV-2 in vivo.

Currently, more than 30 trials of lopinavir and ritonavir treatment of COVID-19 are registered, and according to Clini-calTrials.gov, doses range from 200 to 400 mg of lopinavir and from 50 to 100 mg of ritonavir twice daily (the patients in our analysis received the latter dose for each drug). Unfortunately, lopinavir is almost completely bound by plasma proteins, and only 1% to 2% are free and active (1). To translate drug concentrations in vitro to unbound (and therefore active) This article was published at Annals.org on 12 May 2020. 

concentrations in vivo, a correction for protein binding is required (1, 2) . Unbound drug concentrations of lopinavir are far from reaching the EC50 of SARS-CoV-2 (16.4 μg/mL), although they clearly suffice to inhibit HIV-1.

In conclusion, despite the approximately 2-fold higher lopinavir trough concentrations in our sample of patients with COVID-19 compared with patients with HIV, approximately 60-to 120-fold higher concentrations are required to reach the assumed EC50 at trough levels, making effective treatment of COVID-19 with lopinavir and ritonavir at the currently used doses unlikely. 

Lopinavir/ritonavir: a review of its use in the management of HIV-1 infection

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Clopidogrel in critically ill patients

Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19

 Authors