pharmacokinetics-pharmacodynamics of antiviral …...most agents. in general, the total daily dose...
TRANSCRIPT
Pharmacokinetics-pharmacodynamics of antiviral agents used to treat SARS-CoV-2 and
their potential interaction with drugs and other supportive measures: A comprehensive
review by the PK/PD of Anti-Infectives Study Group of the European Society of
Antimicrobial Agents
Markus Zeitlinger, Department of Clinical Pharmacology, Medical University of Vienna,
Austria
Birgit CP Koch, Hospital Pharmacy, Erasmusmc, Rotterdam, The Netherlands
Roger Bruggemann, Radboud University Medical Center, Nijmegen, The Netherlands
Pieter De Cock, Ghent University Hospital, Department of Pharmacy 2, Ghent University,
Heymans Institute of Pharmacology, Belgium
Timothy Felton, 1. Division of Infection, Immunity & Respiratory Medicine, Faculty of
Biology, Medicine and Health, The University of Manchester, Manchester, UK, 2.
Intensive Care Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust,
Manchester, UK.
Maya Hites, Clinic of Infectious Diseases, CUB-Erasme Hospital, Université Libre de
Bruxelles, Brussels, Belgium
Jennifer Le, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of
California San Diego, San Diego, US
Sonia Luque, 1. Pharmacy Department, Hospital del Mar, Parc de Salut Mar, Barcelona,
Spain 2. Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital
del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Alasdair P MacGowan, Bristol Centre for Antimicrobial Research and Evaluation, Infection
Sciences, Severn Pathology Partnership, North Bristol NHS Trust, Southmead Hospital,
Westbury-on-Trym, Bristol, UK
Deborah JE Marriott, 1. St. Vincent's Hospital, Darlinghurst, New South Wales, Australia, 2.
University of New South Wales, Sydney, Australia
Anouk E Muller, HaaglandenMC, The Hague and ErasmusMC, Rotterdam, The Netherlands
Kristina Nadrah, 1. Department of Infectious Diseases, University Medical Centre Ljubljana,
Ljubljana, Slovenia, 2. Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
David Paterson, 1. University of Queensland Centre for Clinical Research, Faculty of
Medicine, The University of Queensland, Brisbane, Australia 2. Department of Infectious
Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Australia
Joseph F Standing, 1. Infection, Inflammation and Immunity, Great Ormond Street Institute
of Child Health, University College London, UK, 2. Department of Pharmacy, Great Ormond
Street Hospital for Children, London, UK
João P Telles, AC Camargo Cancer Center, Department of Infectious Diseases, São Paulo-SP,
Brazil
Michael Wölfl-Duchek, Department of Clinical Pharmacology, Medical University of Vienna,
Austria
Michael Thy, 1. Infectious diseases department and Intensive care unit, Hospital Bichat, Paris,
France 2. EA7323, Evaluation of perinatal and paediatric therapeutics and pharmacology,
University Paris Descartes, Paris, France
Jason A Roberts, 1. University of Queensland Centre for Clinical Research, Faculty of
Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy,
The University of Queensland, Brisbane, Australia, 2. Departments of Pharmacy and
Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 3.
Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University
Hospital, University of Montpellier, Nîmes France
On behalf of the PK/PD of Anti-Infectives Study Group - EPASG of the European Society of
Antimicrobial Agents (ESCMID), all authors are affiliated with this group.
Key words:
Coronavirus, DDI, Intensive Care, repurposing, off-label, PK/PD, SARS-CoV-2
Running title (40 characters and spaces):
Drugs, PK/PD and DDI for SARS-CoV-2 therapy
Corresponding author: Markus Zeitlinger, Dept. of Clinical Pharmacology, Medical
University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria,
Alternative corresponding author: Jason A. Roberts, The University of Queensland Centre
for Clinical Research, The University of Queensland, Royal Brisbane and Women’s Hospital,
Butterfield St, Herston, Queensland, Australia 4029; [email protected]
40-word summary of the article’s main point:
This review summarizes the current knowledge of available antiviral agents and dosing
considerations for monotherapy and combination treatment of SARS-CoV-2, including
pharmacokinetic and pharmacodynamic data, drug-drug interactions and in vitro and clinical
data.
Abstract:
There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by
SARS-CoV-2. We have conducted a rapid comprehensive review to examine antiviral
pharmacology evidence, focussing on i) the pharmacokinetics (PK) of available or proposed
therapies; ii) coronavirus-specific pharmacodynamics (PD); iii) PK and PD interactions
between proposed combination therapies; iv) a review of the pharmacology of major
supportive therapies; and v) a summary of anticipated drug-drug interactions (DDIs). We
found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir
against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with the combination of
lopinavir-ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against
MERS for post-exposure prophylaxis in healthcare workers. Despite these emerging data,
robust controlled clinical trials remain imperative. These antiviral therapies should be used
with caution in the light of the significant drug interactions and the need to evaluate optimal
doses for treating mild versus serious infections.
Drug active against SARS-CoV-2
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global
pandemic on March 11 2020 and is currently triggering enormous, unrelenting and ever-
increasing demands on health systems in many countries. The number of patients infected
with this novel coronavirus is escalating daily with the first clinical trial for a vaccine initiated
in the United States on March 16, 2020. Meanwhile, the immediate need is to optimize
treatment for infected patients; however, the evidence for therapies against SARS-CoV-2 is
inadequate, leading many medical teams to prescribe drugs based on limited data supporting
their activity, dose or proposed duration of therapy. It is also noteworthy that many drugs are
not uniformly available throughout the world; a therapeutic option for COVID-19 in one
country may not be available in another. Invariably, this heterogeneity of practice and
accessibility may lead to patients receiving sub-optimal therapy because of a lack of
appropriate and readily available data for drugs that are obtainable in a particular country.
Coronaviruses commonly cause infection in non-human animal hosts and, as such, there are
some data available for drugs that may be applicable for use in humans. Along with pre-
clinical data from animal models, there are emerging reports from in vitro cell culture models
which provide information on the mechanism of action and anti-viral effects of tested
compounds. [1] Application of in silico modelling and simulation techniques can then
advance infection model-defined exposure targets to identify doses appropriate for human
use. While this process provides highly valuable direction for anti-viral therapeutic selection
when there is an emergent need for such drugs, these methods are analogous to those applied
in the drug development process. The clinical utility of pre-clinically validated dosing
regimens relies heavily on the available pharmacokinetic (PK) data used in the simulation
process for the particular drug. That is, PK data obtained from healthy volunteers rather than
the population of interest (i.e. severely ill patients with acute respiratory dysfunction
syndrome [ARDS]) may not be applicable due to differences in bioavailability for orally or
subcutaneously administered drugs, and alterations in the drug’s volume of distribution (Vd)
and clearance (Cl) that may result in sub- or supra-optimal exposure; therefore careful
interpretation for clinical use is essential.[2]
Therapeutic agents available for COVID-19 can introduce other treatment challenges,
particularly drug interactions. Various compounds that have been proposed for the treatment
of SARS-CoV-2 are affected by the CYP450-metabolizing system as either substrates,
enzyme inhibitors or enzyme inducers and consideration of these interactions on dosing
requirements of concomitant SARS-CoV-2 or other supportive drug therapies is essential. For
instance, lopinavir/ritonavir (LPV/r) combination has strong inhibitory effects on CYP3A4
and CYP2D6, which also metabolize hydroxychloroquine (another probable agent active
against SARS-CoV-2); this may result in an increase in potential toxic effects. such as
torsades de pointes.[3]
With the significant uncertainty concerning the choice and dose of drug therapy for patients
with active COVID-19 disease, there is a clear need for a review of potential treatments and
interpretation of dosing considerations to optimize treatment based on current evidence. The
aim of this narrative review is to summarize published literature to guide treatment choices in
clinical trials, and to inform local and national policy-makers to enable clinicians to optimize
the treatment regimens for patients outside trials with SARS-CoV-2 infection.
Methods:
Literature regarding the treatment of SARS-CoV-2 is highly dynamic and evolving. Many
results are not yet published in their final form. In order to allow for a fast evaluation of the
most relevant treatment practices at hospitals worldwide, the PK/PD of Anti-Infective Study
Group (EPASG) of the European Society of Clinical Microbiology and Infectious Diseases
(ESCMID) established an e-mail listserv and WhatsApp group for rapid communication. In
addition, the World Health Organization website was evaluated for reports pertinent to our
review.[4]
Once drugs of interest were identified (Table 1) their PK/PD characteristics were summarized
(Table 2). Subsequently, we searched databases to identify single and combination therapies
being evaluated in clinical trials. PubMed and Embase searches (no date limits) were then
performed with the strategy “(drug name) AND (coronavirus)” to identify clinical trials,
retrospective clinical studies, animal or in vitro studies on the drug therapies (Table 3). In
addition, information on drug-drug interactions (DDI) was extracted.[5] Teams of at least 3
authors extracted and agreed upon data presented in each table.
COVID-19 requires intensive care treatment in um to 10% of infected patients. Table 4
therefore presents most commonly used supportive drugs while Supplementary Table 5
present potential interactions of these drugs with antivirals. Unless specifically stated,
Summary of Product characteristics (SmPC) or package leaflets of medications have been
used as the basis for the assessment of DDI. These interactions are also constantly updated on
online platforms, such as the COVID-19 drug interaction webpage maintained by the
University of Liverpool.[3] Extracorporeal support treatments might become necessary under
intensive care treatment of patients with COVID-19. Influence of extracorporeal support
treatments on PK of antivirals is shown in Table 6.
COVID-19 is characterized by lymphocytopenia in most patients, thus combination with
immunosuppressant drugs may be highly problematic at least in early disease. [6] Since
immunosuppressant drugs are not given for treatment of COVID-19 complications, but rather
as potential adjunctive or concomitant therapy, they were not specifically included in this
review.
Results:
Table 1: Antiviral agents for the treatment of COVID-19
Table 1 contains general information about the key drugs currently suggested for the
treatment of COVID-19. Most agents were originally approved for the treatment of other viral
infections. The exception is (hydroxyl)chloroquine, an immunomodulatory drug with known
antiviral activity but that has been used primarily for over 60 years to treat malaria and, more
recently, autoimmune diseases, such as systemic lupus erythematosus and inflammatory
arthritis. Some of the agents listed have been studied with related viruses, such as Middle East
Respiratory Syndrome coronavirus (MERS). Most agents have unique mechanisms of action
against SARS-CoV-2. As COVID-19 has emerged only recently, all drugs are in various
phases of clinical trials. None of these drugs are approved for COVID-19; the dosing
regimens are based on current knowledge, derived from other indications and may change in
the future when new data become available. Dosing regimens in children are unavailable for
most agents. In general, the total daily dose of the regimens used for COVID-19 is similar to,
or greater than, that used for other indications.
Table 2: PK/PD of antiviral agents for the treatment of COVID-19
Table 2 summarizes the data on the PK/PD properties of the agents recommended for SARS-
CoV-2 and other viruses. The available data are limited and based primarily on in vitro
studies in various cell-lines. The effect is usually presented as the half-maximal effective
concentrations (EC50) which varies between viruses. The EC50 values for other viruses are
included in the table in order to compare the efficacy against SARS-CoV-2, with a lower
EC50 corresponding to increased potency. Data on other coronaviruses have been
summarized; however, where data are unavailable for coronaviruses, other pathogens are
reported. For chloroquine and PegINF-α2β, measured intracellular concentrations are
correlated with the in vitro EC50 and, as such, serve as the PK/PD index.[7, 8] However,
there are no studies comparing various PK/PD indices for these agents.
The EC50 values for remdesivir, chloroquine and ribavirin against SARS-CoV-2 were
compared with those of MERS. For both remdesivir and ribavirin, the EC50 values were
higher than for MERS, indicating that a larger dose may be needed to treat COVID-19. The
EC50 value of chloroquine was within the same range for SARS-CoV-2 and MERS. Yao et
al. compared chloroquine with hydroxychloroquine in an in vitro study and reported that
hydroxychloroquine was more potent than chloroquine [8], although caution interpreting these
results is warranted since different EC50 values were reported depending on whether
experiments were conducted for 24 or 48 hours. Since EC50 is not a time-dependent
parameter, this calls into question how reliable the estimate is and how well it may translate to
an in vivo target. Nevertheless, based on these results and physiologically-based
pharmacokinetic (PBPK) modelling, a loading dose of oral hydroxychloroquine sulfate 400
mg twice daily, followed by a maintenance dose of 200 mg twice daily for 4 days was
recommended for the treatment of COVID-19 [8], and this may at present provide our best
estimate of optimal dose. Several interferons including IFN-α, PegIFN-α2β, IFN-α1β and
IFN-β1β, have been examined for the treatment of COVID-19; however, they are not
administered as monotherapy but as adjuvant therapy with other anti-COVID-19 drugs.
The currently available data on drug efficacy and PK/PD targets for COVID-19 are
inadequate to support therapeutic drug monitoring. However, some data on plasma
concentrations are available in the literature (Table 2). When drug concentrations are
available in the literature, it may be prudent to evaluate individual concentrations in
exceptional patients such as those undergoing extracorporeal membrane oxygenation
[ECMO].
Table 3: Combination SARS-CoV-2 antiviral agents and associated DDI
As there are no approved SARS-CoV-2 therapies, combination therapy with agents utilizing
different modes of action may be administered in an attempt to optimize therapy until clinical
trial data become available. This combination approach is consistent with the management of
many viral, fungal and bacterial infections with sub-optimal treatment options. We aimed to
assess the evidence of repurposed antiviral combinations that were not specifically designed
to treat SARS-CoV-2.
The strongest evidence exists for LPV/r plus ribavirin therapy (retrospective, case-control
study) resulting in a reduction in mortality, acute respiratory distress syndrome (ARDS), and
viral shedding in the treatment of SARS (Table 3). However, extrapolating these data to
SARS-CoV-2 should be undertaken with caution as LPV/r and another HIV protease
inhibitor, nelfinavir, exhibit good activity against SARS [9, 10] but are less effective against
MERS.[11] Of note, we found no clinical data on (hydroxyl)chloroquine combinations;
randomised trials involving these drugs, based on their promising in vitro activity, will
provide important guidance.
We deliberately excluded analysis of combinations with remdesivir since the currently open
trials investigate only monotherapy.
Table 4: Most commonly used supportive agents (ICU, pain, fever, anticoagulation)
Supportive care with other pharmacological agents, including antibiotics, sedatives,
analgesics, and anticoagulants, need to be considered when treating with antiviral and other
re-purposed agents, particularly in the critical care setting. Table 4 lists the major drugs by
class and highlights potential interactions. In particular, caution should be exercised for
CYP3A4 DDIs with narrow therapeutic index drugs, such as anticoagulants (warfarin,
acenokumarol, dabigatran, rivaroxaban, and apixaban) and immunosuppressant agents in
transplant recipients in whom additional monitoring may be required. For patients sedated
with midazolam, dose reduction should be considered when patients are treated with CYP3A4
inhibitors, such as LPV/r and darunavir/cobicistat as there is a significant risk of over sedation
resulting in unnecessary prolongation of ICU stay.[12] There are multiple potential
interactions resulting in cardiac complications, including prolonged QT interval with
(hydroxyl-) chloroquine combinations, LPV/r and darunavir/cobicistat that necessitates
monitoring. As these DDI are substantial, the balance of risk versus benefit should be
carefully considered prior to drug administration to prevent significant morbidities.
Table 5 a+b: Interaction between antivirals presented in Table 1 and supportive drugs
presented in Table 4.
The relevant interactions are provided for most drugs used for COVID-19 and co-medications
in detail in Supplementary Tables 5a and 5b.
DDI are an important consideration with all therapies used to treat COVID-19. This is
especially the case with repurposed antiretroviral drugs and aminoquinolines, such as
(hydroxy)chloroquine, which have many interactions when administered with other
medications. Since hydroxychloroquine currently seems to be the most frequently used drug
to treat COVID-19 it was separately reviewed in great detail in table 5a while DDI with other
antivirals were concisely summarized in table 5b. Clinicians treating patients infected with
SARS-CoV-2 need to carefully consider the potential for DDIs before commencing therapy.
Many DDIs may be mitigated by simple measures such as continuous ECG monitoring. The
ritonavir component of LPV/r, and similarly the cobicistat component of darunavir/cobicistat,
are deliberately used to inhibit CYP3A4 and thereby increase antiretroviral drug
concentrations. However, this leads to a significant potential to increase concentrations of
other co-administered therapies. Notably, the interaction between (hydroxy)chloroquine and
other agents that may inhibit drug clearance can result in cardiac toxicity and patients should
be monitored closely. This may be especially problematic in critically-ill patients with pre-
existing cardiovascular morbidity and extreme caution should be observed. The use of
triazoles should be avoided or carefully monitored if administered concurrently with LPV/r or
darunavir/cobicistat due to DDI. Potential DDI are reported between either LPV/r and
darunavir/cobicistat and important drugs commonly used in the critical care setting. including
ketamine, rocuronium and many of the opioid agents. Utmost care is required when
considering the co-administration of these agents with the anti-retroviral drugs in critically-ill
patients. The newer investigational antiviral agents, remdesivir and favipiravir, may have a
lower potential for DDIs. However, the main concern with their use is decreased
concentrations if co-administered with enzyme inducers. Chloroquine and
hydroxychloroquine are known to prolong the QT interval; therefore, ECG monitoring is
required when they are co-administered with agents known to cause QT-interval prolongation.
Co-administration of (hydroxy)chloroquine with drugs which are known to prolong the QT
interval, such as amiodarone and flecanide, is not recommended. However, clinical
experience with these drugs is much less than the repurposed antiretrovirals. A comprehensive
and evolving DDI database has been created by the University of Liverpool and this should be
consulted for potential DDIs not covered in our review.[3]
Table 6: The effect of extracorporeal treatments on the pharmacokinetics of COVID-19
therapies
Generally, the volume of distribution (Vd) is low for hydrophilic drugs and high for lipophilic
drugs. Systemic inflammatory responses (SIRS) may occur with use of extracorporeal
treatments and cause alterations in cytochrome P450 (CYP)‐mediated metabolism. The effect
of CYP activity by SIRS is increased activity for all CYPs, except 3A4 which decreases. In
children, CYP enzymes are commonly immature in neonates and take time to reach similar
activity levels to adults [13]. In this section, we summarize the principles of PK alterations
that occur with ECMO and renal replacement therapy (RRT) to impact drug exposure and
thereby dose. Although limited studies have been conducted on COVID-19 therapies,
optimized dosing should consider these potential impacts on individual patients.
The impact of ECMO
The most common mechanisms by which ECMO affects PK of drugs are sequestration by the
oxygenator and tubing in the ECMO circuit to result in decreased drug clearance (CL) [13].
While lipophilic drugs and highly protein-bound drugs are more likely to be sequestered in
the circuit, hydrophilic drugs are can be significantly affected by hemodilution and changes in
albumin concentration, potentially leading to altered protein binding and an increased Vd.
Indeed, an increased free fraction means more distribution from the central into the peripheral
compartments (i.e., tissues) leading to an increased apparent Vd [14].
The impact of renal replacement therapy
Sepsis-related acute kidney injury often develops in the context of multiple organ dysfunction
syndrome and leads to relevant modifications of several PK parameters. Moreover, high
volumes of fluid resuscitation, commonly required in critically ill patients [15], may
significantly affect the Vd of several drugs [16]. When Vd of a drug is typically small since
the drug is mostly retained in the intravascular compartment (where protein binding is not
high), clinically significant removal of small drugs by RRT is likely. In this context, the
commencement of RRT adds further complexities for dosing with the associated additional
extracorporeal CL of many antimicrobial agents. Renally excreted drugs are usually affected
by RRT to a much greater extent than hepatically excreted drugs [17]. Only the free (i.e.,
unbound) drug is cleared across the RRT filter. With the exception of a few drugs, the
molecular weight (MW) of most commonly used antimicrobial agents is lower than 1,000 Da
and plays a key role, especially in diffusive RRT modalities, as the sieving coefficient (SC) of
a molecule is inversely proportional to MW. The SC is generally similar for drugs with MW
around 1,000 to 1,500 Da in convective modalities. However, in diffusive techniques, the
ratio of dialysate to plasma solute concentration (saturation coefficient [SA]) is more strictly
dependent on MW and tends to decrease progressively as MW increases [18]. Whereas
intermittent hemodialysis (IHD) is essentially a diffusive technique and CVVH is a
convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of
drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but
this can still vary greatly depending on the physicochemical properties of each drug and the
CRRT’s settings [19]. Dialyzer membrane characteristics (cutoff) may also play a key role.
Pharmacokinetic data of drugs active against SARS-CoV-2
Table 6 extrapolates basic drug physicochemistry and known PK data to predict the likely
effects of ECMO on PK. Data on the hemodialysis clearance of (hydroxy)chloroquine are
available and suggest that the high Vd of (hydroxy)chloroquine limits significant alteration in
drug concentrations.[20] As such, ECMO is predicted to have minimal impact on the drug
concentrations of (hydroxy)chloroquine, although sequestration onto the oxygenator and
circuit tubing cannot be excluded. There is also the hypothesis that (hydroxy)chloroquine
rapidly partitions into the intracellular space, potentially resulting in minor effects overall and
in the vascular compartment.[15] The PK of LPV/r in hemodialysis suggests that dosing
adjustments are unnecessary in treatment-naive patients, in part due to the high protein
binding of these drugs [21]. CVVH has no clinically relevant contribution to total CL of
favipiravir [22]. For ribavirin, CL was reduced by 50% via IHD [23] which is not be
considered significant enough to justify increasing the dose based on increases in dialysate or
RRT filtration flow rate.[24] No significant effect of RRT on IFN concentration is predicted
due to the MW of the IFN compounds which usually exceed 15 kDa. [25, 26]
Discussion:
We have provided an in-depth rapid review on the preclinical and clinical antiviral treatment
options for SARS-CoV-2. It should be emphasized that although the approach in the current
review is pragmatic to allow for real-time assessment of the international practice, it cannot
guarantee that all experimental combinations have been captured. However, the therapeutic
investigations for COVID-19 is highly dynamic and almost daily new treatment options are
empirically tested in clinical practice globally. More importantly, the quality of data regarding
the safe and effective use of treatment options are generally poor and strong recommendations
cannot be provided regarding the superiority of one treatment or combination over another. It
is clear with absolute certainty that robust controlled clinical trials are imperative. These
antiviral therapies should be used with caution due to the significant drug interactions and the
need to evaluate optimal doses for treating mild versus serious infections.
All drugs presented in Table 1 should be seen as possible treatment options for patients
suffering or very likely to develop a critical COVID-19 disease despite no official
recommendations being available. We found that PK/PD indices indicate that many of the
currently used treatment regimens fail to achieve sufficient concentrations when EC50 values
are compared with plasma PK, which might partially explain limited clinical success of these
combinations. Before investigation of any new combination empirically, PK/PD models with
Monte Carlo simulations should be used to predict success and, wherever possible, integrate
an adaptive design to also account for tolerability. Failure to develop these models might lead
to suboptimal drug exposure in patients, resulting in erroneous omission of therapeutic
options before exploring their full potential.
Relevant DDI exist both between combinations of antivirals and also between antivirals and
supportive therapies. Since many of the combinations have not been widely used in ICU,
healthcare providers should be alerted to closely monitor for DDI. With the omnipresent work
overload related to COVID-19 crisis within hospitals and ICUs, apps or programs should be
developed to support real-time clinical decisions and dose adaption.
A recent study of LPV/r showed no effect against SARS-CoV-2 [27], but this conclusion
should be interpreted with caution. Only 199 patients were randomized and the non-
significant trend showed a 5.8% decrease in mortality with LPV/r versus no treatment. If this
is the true effect size, a larger sample size is required. Furthermore, the high overall mortality
reported in this study suggest that these patients had severe disease and the late initiation of
therapy (i.e., within 12 days after the onset of symptoms) may have affected the results. As
such, the clinical benefit of early initiation of LPV/r monotherapy should be further
investigated. In addition, the clinical trials of SARS or MERS evaluated LPV/r in
combination with ribavirin, rather than as monotherapy. Lopinavir and ribavirin have been
found to be synergistic in vitro against SARS [9], and, more importantly, the combination of
LPV/r and ribavirin reduced mortality and viral shedding when compared with historical
controls [9]. Another study in SARS reported that early initiation of combination therapy
consisting of LPV/r plus ribavirin, as compared with historical controls treated with ribavirin
alone, significantly reduced mortality and the need for ventilation; notably, there was no
effect with delayed or late therapy.[28] LPV/r plus ribavirin also significantly reduced, from
28.6% to zero, the transmission of MERS amongst healthcare workers with unprotected
encounters. Extrapolating these data to SARS-CoV-2 should be taken with caution since LPV
and the protease inhibitor nelfinavir appears to exhibit good activity against SARS [10], but
are less effective against MERS.[11] Nonetheless, LPV/r plus ribavirin should be investigated
for in vitro synergy against SARS-CoV-2 and considered for clinical evaluation if results are
promising. Of note, we found no clinical data on (hydroxy)chloroquine combinations; clinical
trials evaluating these drugs are prudent due to their promising in vitro activity and emerging
monotherapy data.
In summary, there are promising therapeutic options for COVID-19 and in the absence of a
vaccine at present, it is highly likely that one of the agents mentioned in this review, or more
plausibly a combination, may emerge as a prophylactic or early treatment option with the
potential to decrease viral shedding and transmission and/or reduce disease progression to the
requirement of ventilatory support. While some readers will seek to use information in this
review to choose available therapies to treat patients currently hospitalised with SARS-CoV-
2, perhaps of greater importance is that our data are used to guide treatment regimens in large
scale adaptive trial designs that will provide definitive answers on effect sizes. The prize is to
find an antiviral, or likely as with many other infectious diseases, a combination of antiviral
agents, which limit both transmission and disease progression to a sufficient extent to relax
some of the social restrictions that have been mandated throughout the globe.
Due to the lack of highly effective and sufficiently evaluated treatment options, the most
important strategy currently is avoidance of infection by the implementation of optimal public
health measures that incorporate appropriate handwashing and social distancing. Furthermore,
the use of rapid diagnostic tests to identify silent carriers, along with active disease, and
availability of personal protective equipment to protect from transmission are critical to limit
the massive spread of infection. Lastly, the development of vaccines (in which a clinical trial
has been initiated in the United States) is vital to immediately protect individual immunity
and our global community long-term.
Funding:
No funding was received for this manuscript.
Conflict of Interest
The authors declare that they have no conflict of interest associated with the content of the
current manuscript.
Acknowledgments
The review was performed by members of the PK/PD of Anti-Infectives Study Group
(EPASG) of the European Society of Clinical Microbiology and Infectious Diseases
(ESCMID)
JFS was funded by a United Kingdom Medical Research Council Fellowship
(MR/M008665/1). JAR would like to acknowledge funding from the Australian National
Health and Medical Research Council for a Centre of Research Excellence (APP1099452)
and a Practitioner Fellowship (APP1117065).
Tables:
Table 1. Antivirals and supportive drugs used to treat COVID-19
Substance Generic name
Normal approved indication
Studied virus Study phase for COVID-19a
Antiviral Mode of action
Supplier/ Major countries where available
Currently used dose for approved indication (mg)
Adult dosing in COVID-19 (mg)
Children dosing in COVID-19 (mg)
Route of administrat-ion
Route of elimination
Remdesivir
Antiviral under investigation
COVID-19, MERS-CoVb, SARS-CoVc, HCoV-229Ed, HCoV-OC43e Phase III
Viral RNAf polymerase inhibitor
Gilead® Europe USA
200mg on day 1, followed by 100mg/day (total 10-14 days)
200 mg on day 1 followed by 100mg/day on days 2-10
WT:<40 kg: 5 mg/kg load, then 2.5 mg/kg/24h WT:≥40 kg: 200 mg load, then 100 mg/24h[29] IVg n.a.h
Chloroquine Approved antimalarial
COVID-19, SARS-CoV, HCoV-OC43
Cell cultures/co-cultures; Phase III
Inhibition of endosome-mediated viral entry, and pH dependent steps in viral replication [30]
Sanofi-Aventis® Global 100 mg/24h
600mg/12h on day 1, followed by 300 mg BID on days 2-5; alternative: 500mg/12h during 5 days [8] n.a. ORi or IV
50% renal clearance (excreted unchanged in the urine); metabolized by CYP2C8, CYP3A4 and to lesser extent CYP2D6
Lopinavir Approved antiviral
COVID-19, MERS-CoV Phase IV
HIV protease inhibitor
Abbott® Global 400 mg/12h
LPV/rj 400/100mg/12h OR, 14 days[27]
(a) age:14d-12m: 16 mg/4 mg (LPV/r)/kg/12h
OR metabolized by CYP3A
Ritonavir Approved COVID-19, Phase IV HIV Abbott® 100 mg/12h LPV/r OR CYP3A4 and
antiviral MERS-CoV protease inhibitor/ Boost of other protease inhibitors.
Global 400/100mg/12h OR, 14 days[27]
(b) age 12m-18y: (i) WT <15 kg: 13 mg/3.25 mg (LPV/r)/ kg/12h; (ii) WT ≥15 to 40 kg: 11 mg/2.75 mg (LPV/r)/kg/12h[31]
to a lesser extent CYP2D6 [32]
Favipiravir Approved antiviral COVID-19 Phase II
Viral RNA polymerase inhibitor
Fujifilm Toyama Chemical ® China, Japan
1600 mg/12h on day 1 then 600 mg/12h on days 2-5 Under study n.a.
OR; IV under development [33]
Genetic variant in digestive transport [P-gpk; ABCB1] and metabolism [aldehyde oxydase] to an inactive M1, urinary excretion; both metabolized by and inhibited byaldehyde oxidase [33]
Ribavirin Approved antiviral COVID-19
Cell cultures/co-cultures
Unclear: Multiple possible mechanismsl
Generic Europe
400-600mg/12h
500 mg/12h or 500mg/8h IV [34] n.a.
aerosol, OR or IV
Renal clearance (30%), some fecal excretion
Arbidol/ Umifenovir
Approved antiviral COVID-19 Phase IV
Inhibits membrane fusion, stimulation
Russian Research Chemical Pharmace 50-200mg/6h 200 mg/8h [34]
Safety unclear [35] OR
Via the feces, metabolized in hepatic and intestinal
of immune system
utical Institute Russia, China
microsomes (33 metabolites known), CYP3A4[36]
Hydroxy-chloroquine
Approved antimalarial COVID-19
Phase III (NCT04261517)
Inhibition of endosome-mediated viral entry, and pH dependent steps in viral replication [30]
Sanofi-Aventis® Europe 100 mg/24h
400 mg/day for 5 days (NCT04261517) OR 400 mg/12h on day 1 followed by 200 mg/12h on days 2-5 [8] n.a. OR
50% renal clearance (excreted unchanged in the urine); metabolized by CYP2C8, CYP3A4 and to lesser extent CYP2D6
PegIFN-α2β Approved antiviral
COVID-19, MERS-CoV, HCoV
Phase IV (NCT04254874;NCT04291729)
Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms
- Europe
1.5 μg/kg/ week SC
45-50 μg/12h (NCT04254874;NCT04291729) n.a.
Nebulized; SC
Renal clearance [37]
IFN-α1β Approved antiviral
COVID-19, MERS-CoV, HCoV
Early phase I (NCT04293887)
Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms
- China -
10 μg/12h (NCT04293887) n.a. Nebulized
Renal clearance [37]
IFN-α Approved antiviral
COVID-19, MERS-CoV, HCoV
Not applicable (NCT04251871) [38]
Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms
- China -
5 million IU/12h (NCT04251871; [38])
Interferon-α 200,000– 400,000 IU/kg or 2–4 μg/kg in 2 mL sterile water, nebulization Nebulized
Renal clearance [37]
two times per day for 5–7 days [35]
IFN-β1β Approved antiviral
COVID-19, MERS-CoV, HCoV
Phase II (NCT04276688)
Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms
- Europe, China
25 μg SC injection alternate day
25 μg SC injection alternate day for 3 days (NCT04276688) SC
Renal clearance [37]
aCOVID-19: Coronavirus disease 2019; bMERS-CoV: Middle East Respiratory Syndrome coronavirus; cSARS-CoV: severe acute respiratory syndrome
coronavirus 2; dHCoV-229E: Human coronavirus 229E; eHCoV-OC43: Human coronaviruses Subtype OC43; fRNA: Ribonucleic acid; gIV: intravenous, hn.a.:
not available; iOR: Oral; jLPV/r: Lopinavir/ritonavir; kP-gP: Permeability glycoprotein; lUnclear: Multiple possible mechanisms. 1) immunomodulatory effect 2)
inhibition of inosine monophosphate dehydrogenase 3) inhibition of nucleic acid polymerases thereby inhibiting viral transcription 4) prevention of capping of
mRNA, resulting in inefficient translation of viral transcripts 5) increase of mutation rate of RNA viruses, resulting in ‘error catastrophe’ [39]
Table 2: PK/PD of antivirals and other drugs used to treat COVID-19
Drug PDa metric (e.g. IC50b)
Type of study used for
COVID-19c experiments
EC50d/EC90e for COVID-19
(μM)
EC50/EC90 for other indications
Blood concentrations
Remdesivir EC50
In vitro (vero E6 cells)
0.77 [40] 0.09 μM (MERS-CoV)f in mice model
[41] 10 μM in nonhuman primates was reached after a dose of 10 mg/kg IV [42]
EC90 In vitro
(vero E6 cells)1.76 [40] n.a.g
Chloroquine EC50
In vitro (vero E6 cells)
1.13-5.47 [8, 40]
0.05 μM (P.vivax) in vitro [43]; 3.1 μM (HIV)h in vitro [44];
3.0 μM (MERS-CoV) in vitro [45]; 4.1 μM (SARS-CoV)i in vitro [45]
A concentration of 6.9 μM is achievable in patients after a 500 mg dose [40, 46]. However, concentrations as low as 0.5-1.0 μM were also demonstrated after 300mg/12h regimen [47]
EC90 In vitro
(vero E6 cells)6.9 [40]
0. 358 μM (P. vivax) in vitro at 30h [43]
Lopinavir/Ritonavir EC50 n.a. n.a.
LPV: 8-11.6 μM (MERS-CoV) in mice/vitro [41, 45];
LPV: 17.1 μM (SARS-CoV) in vitro [45]
Ritonavir: 24.9 μM (MERS-CoV) in mice model [41]
LPV/r: 8.5 μM (MERS-CoV) in mice model [41]
LPV Cmax values average 12.72 μM (with p2.5 of 6.36 μM to p97.5 of 23.85 μM) and ritonavir Cmax values average 0.7 μM (with p2.5 of 0.2
μM to p97.5 of 2.22 μM). [48]HNote: treatment outcomes were no
different from standard of care inhospitalised patients with COVID-19[27]
Favipiravir IC50 In vitro
(vero E6 cells) 61.88 [40] 67 μM for Ebola [49]
Concentrations of 1190 ± 478 μM were achieved 1h after Favipiravir 400mg loading
dose in nonhuman primates [50]. Median total trough (pre-dose) and average concentrations of
360 and 520μM respectively following 1200 mg/12 hours with a loading dose of 6000 mg in
Ebola-infected patients [51] with a fall in average concentration on day 4. Non-linear PK
Ribavirin EC50 In vitro
(vero E6 cells)109.50
[40] 40.94 ± 12.17 μM (MERS-CoV) in
vitro [11]
Concentration range between 25.0-10.65 μM achieved with ribavirin dose regimen of 400-
600mg/12h [52]
Arbidol (Umifenovir)
EC50 n.a. n.a. 24.72 μM (Avian infectious bronchitis
virus as representative for Coronaviridae) [53]
Concentrations of 1.47, 2.60 and 4.53μM achieved after 0.2, 0.4 and 0.8g doses [54]
Hydroxychloroquine EC50 In vitro
(vero E6 cells)0.72 μM [2]
Concentration >1.49 μM (>500 ng/ml) achievable following 6mg/kg/day dosing
regimen [55]
Concentration shown to
reduce viral titers
80 μM (Zika Virus) in vitro [56]
PegINFl-α2β ** EC50 n.a. n.a. 0.04 μg/L (HCVm patients) [7] Cmax of 0.53 μg/L in patients after 1.5 μg/kg
SCn [57]
INF-β1β ** EC50 n.a. n.a. 17.64 ± 1.09 UI/ml (MERS-CoV)[11], 1.37 U/ml (MERS-CoV) [58]
Concentration of 240 UI/ml following 8 Million IUSC [59]
INF-β1β ** EC90 n.a. n.a. 38.8 U/ml (MERS-CoV) [58]
aPD: pharmacodynamics; bIC50: half maximal inhibitory concentration; cCOVID-19: coronavirus disease 2019; dEC50: half maximal effective concentration;
eEC90: 90% effective concentration; fMERS-CoV: Middle East Respiratory Syndrome coronavirus; gn.a.: not available; hHIV: human immunodeficiency viruses;
iSARS-CoV: severe acute respiratory syndrome coronavirus 1; jLPV/r: lopinavir/ritonavir; kCEK: chicken embryo kidney; lINF: interferon; mHCV: hepatitis C
virus; nSC: subcutaneous.
Table 3. Drug-drug interactions of proposed anti-viral combinations against coronavirus
Proposed combination (with clinical trial reference if available)
Pharmacodynamic rationale
Drug-drug interactions with level of severity and therapeutic advice[60]
Level of evidence 1. Clinical trial in a coronavirus 2. Retrospective clinical data 3. In vivo animal or in vitro data
Lopinavir + Ritonavir (LPV/ra) [61]
Inhibition of replication (i.e., ritonavir boosting lopinavir)
Strong inhibition of CYP3A-mediated metabolism of lopinavir (3-fold AUCb increase) for therapeutic boosting Level of severity: wanted interaction
1. Clinical trial: No effect on mortality or viral load in 199 COVID-19c patients randomized 1:1 to LPV/r versus standard of care.[27] A further 8 randomized controlled trials are currently registered for COVID-19 2. Retrospective clinical data: Case reports in 4 patients with SARS-CoV2d receiving LPV/r demonstrated decreased viral load and ¾ patients had symptomatic improvement. No data on LPV/r monotherapy in retrospective comparisons for SARS-CoVe and MERS-CoVf
[62] 3. In vivo animal or in vitro data: a. In vitro antiviral susceptibility testing demonstrated inhibition of cytopathic effects of SARS-CoV at concentrations of 4 µg/ml ( ) and 50 µg/ml of ritonavir after 48 h[9] b. In Vero cell line, the EC50 for plaque reduction of SARS-CoV was 6 µg/ml[63] c. Molecular dynamic simulations indicated that SARS-CoV 3CL pro- enzyme could be inhibited by LPV/r[64] d. Efficacy of lopinavir against SARS-CoV may be poor because 50% of LPV remains outside the catalytic site of the main protease (demonstrated by binding analysis)[65] e. LPV was shown to have poor antiviral activity against MERS-CoV in 2 in vitro studies[11, 41], but effective in another study at 12 µM[45] f. LPV/r treated marmosets with MERS-CoV had better clinical scores, reduced pulmonary infiltrates and lower viral load in the lungs of treated animals vs. controls[66] Theoretical interaction: a. Antiviral activity of LPV/r is similar to that of LPV alone, suggesting effect is driven by LPV[9, 41]
Ribavirin + LPV/r Inhibition of Increased risk of liver 1. Clinical trials: no data
[67]
replication PLUS inhibition of RNA synthesis
toxicity Level of severity: major Therapeutic advice: monitor for increased liver toxicity
2. Retrospective clinical data: a. Retrospective matched cohort study for SARS-CoV infection: 41 cases treated with LPV/r + ribavirin vs. 111 historical controls treated with ribavirin alone; better clinical outcome (ARDSg and death) at day 21 after onset of symptoms: 2.4% vs. 28.8%; p<0.001. No difference in outcome reported for early vs. delayed treatment[9] b. Multicentre retrospective matched cohort study for SARS-CoV infection: 75 cases treated with LPV/r + ribavirin vs. 977 controls treated with ribavirin. Reduction in death (2.3% vs. 15.6%; p<0.05) and intubation (0% vs. 11%; p<0.05) was evident only in the sub-group of initial treatment with LPV/r; no significant difference in the late treatment group [28] c. MERS-CoV infection: post-exposure prophylaxis with ribavirin + LPV/r in 43 healthcare workers resulted ina 40% reduction in the risk of MERS-CoV infection with no severe adverse events during treatment[68] 3. In vivo animal or in vitro data: In vitro checkerboard assay for synergy on SARS-CoV demonstrated inhibition of the cytopathic effect with a concentration of LPV of 1 μg/ml with ribavirin 6.25 μg/ml when the viral inoculum was < 50 median tissue culture infectious dose [9, 63]
LPV/r + Arbidol [67]
Inhibition of replication PLUS Inhibition of RNA synthesis PLUS Inhibition of viral entry
No clinical data available. CYP3A4 is major pathway of metabolism for arbidol; strong inhibition of CYP3A4-mediated metabolism of arbidol by ritonavir is plausible. Level of severity: unknown Therapeutic advice: monitor for increased
1. Clinical trials: no data 2. Retrospective clinical data: Case series (n=4) of mild or severe COVID-19 pneumonia successfully treated with LPV/r + arbidol + Shufeng Jiedo Capsule (traditional Chinese medicine)[69, 70] 3. In vivo animal or in vitro data: no data
toxicity of arbidol (17)
Chloroquine + LPV/r Inhibition of replication PLUS Inhibition of viral entry
Increased risk of QTch prolongation (potentially dangerous interaction) Inhibition of CYP3A-mediated metabolism of chloroquine by ritonavir Level of severity: major Therapeutic advice: monitor ECGi and monitor for increased toxicity of chloroquine if used in combination. Dose reduction of chloroquine might be necessary in case of severe toxicity.
1. Clinical trials: no data, but ongoing open-label study currently in China (ChiCTR2000029741)[62] 2. Retrospective clinical data: no data 3. In vivo animal or in vitro data: no data
Darunavir (with Cobicistat) [71]
Inhibition of replication (cobicistat has no antiviral effect, only inhibits darunavir metabolism to increase concentration)
Strong inhibition of CYP3A4-mediated metabolism of darunavir by cobicistat for therapeutic boosting Level of severity: wanted interaction
1. Clinical trials: no data but ongoing trial currently (Phase 3: NCT04252274)[72] 2. Retrospective clinical data: no data 3. In vivo animal or in vitro data no data
Emtricitabine + Tenofovir (Truvada)
Inhibition of RNA synthesis (dual
No data 1. Clinical trials: no data
therapy) 2. Retrospective clinical data: no data 3. In vivo animal or in vitro data: no data
Emtricitabine + Tenofovir (Truvada) + LPV/r [73]
Inhibition of replication PLUS Inhibition of RNA synthesis
Increased tenofovir absorption (i.e., 32% AUC increase; 51% Cminj increase) through P-glycoprotein inhibition Level of severity: moderate Therapeutic advice: monitor for tenofovir-associated toxicity
1. Clinical trials: no data 2. Retrospective clinical data: no data 3. In vivo animal or in vitro data: no data
Interferon + Ribavirin Immune modulation PLUS Inhibition of RNAk synthesis
No data 1. Clinical trials: no data 2. Retrospective clinical data: Multicenter observational study in critically ill patients with MERS-CoV infection. Of 349 MERS-CoV infected patients, 144 received RBV/rIFNl (rIFN-α2a, rIFN-α2b or rIFN-ß1a). Treatment was not associated with reduction in 90-day mortality, nor faster MERS-CoV RNA clearance[72] b. Retrospective cohort study of patients with MERS-CoV requiring ventilation support who received supportive care (n= 24) vs. oral ribavirin + pegylated IFN-α2a (n=20). Treatment with ribavirin + IFN-α2a was associated with significantly improved survival at 14 days, but not 28 days[74] 3. In vivo animal or in vitro data: (3,14,15) Synergistic antiviral effect between ribavirin and Type I IFN (i.e., IFN-α [63, 75], or IFN-ß[63, 75, 76]) on SARS-CoV was described in 2 studies performed in human and Vero cell lines
LPV/r + Interferon + Ribavirin
Immune modulation PLUS Inhibition of RNA synthesis PLUS Inhibition of
Level of severity: major Therapeutic advice:
1. Clinical trials: no data 2. Retrospective clinical data: case report, patient recovered[77]
replication monitor for increased risk for hepatotoxicity (for combination protease inhibitor + ribavirin and protease inhibitor + interferon)
3. In vivo animal or in vitro data: no data
Hydroxychloroquine + azithromycin
Immune modulation PLUS Inhibition of viral entry
Increased risk of QTc prolongation (potentially dangerous interaction) Level of severity: Major Therapeutic advice: monitor ECG
1. Clinical trials: One open-label, non- randomized clinical study in 36 patients with confirmed SARS-CoV2 infection (interim analysis of ongoing trial)[78] Of 36 patients, 14 received hydroxychloroquine treatment, 6 received hydroxychloroquine/azithromycin combination treatment and 16 were controls. The proportion of patients with negative PCRm in nasopharyngeal samples was significantly higher in hydroxychloroquine treated patients at day 3-4-5 and 6 post-inclusion versus control patients. If hydroxychloroquine were used in combination with azithromycin, the proportion of patients with negative PCR in nasopharyngeal samples was significantly higher on days 3-4-5 and 6 when compared with patients treated with hydroxychloroquine monotherapy.
2. Retrospective clinical data: no data
3. In vivo animal or in vitro data: no data
aLPV/r: Lopinavir/ritonavir; bAUC: area under the curve; cCOVID-19: coronavirus disease 2019; dSARS-CoV: severe acute respiratory syndrome coronavirus 2;
eSARS-CoV: severe acute respiratory syndrome coronavirus; fMERS-CoV: Middle East Respiratory Syndrome coronavirus; gARDS: Acute respiratory disease
syndrome; hQTc: corrected QT interval; iECG: electrocardiogram; jCmin: trough concentration; kRNA: Ribonucleic acid; lRDV/rIFN: Ribavirin + Recombinant
Interferon; mPCR: Polymerase chain reaction.
Table 4: Most commonly used supportive drugs
Generic name Indication CYP substrate CYP inhibitor/inducer
Transporters Other metabolism
Comment Reference
ACE inhibitors
Captopril Arterial hypertension none OAT1 substrate
captopril disulphide and captopril cysteine disulphide in 50%
[79-81]
Enalapril Arterial hypertension none OATP1a1 substrate
hydrolysed to enalaprilate
[81-83]
Perindopril Arterial hypertension none hydrolysed to perindoprilate by hepatic esterase
Some ACEI undergo CYP3A4 bioactivation (animal studies), but no interactions known.
[81, 84]
Angiotensin II receptor antagonists
Irbesartan Arterial hypertension CYP2C9 CYP2C9 inhibitor
[81]
Losartan Arterial hypertension CYP2C9, CYP3A4 (minor)
CYP2C9 inhibitor
[81]
Valsartan Arterial hypertension none
substrate of OATP1B1/OATP1B3, hepatic efflux transporter MRP2 and OAT1
substrate for OATP1B1/OATP1B3, hepatic efflux transporter MRP2
[80, 85]
Anticoagulants
Acenokumarol Anticoagulation CYP2C9 (major), CYP1A2 and CYP2C19
Inhibitors of CYP2C9 may potentiate, inducers of CYP2C9, CYP2C19 or CYP3A4 may diminish the anticoagulant effect. Monitoring INR recommended.
[86, 87]
Apixaban Anticoagulation
CYP3A4/5 (main), CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 (minor).
substrate of P-gp and BCRP
Inducers of CYP3A4 diminish, inhibitors of CYP3A4 and P-gp increase exposure; not recommended only with strong inhibitors of CYP3A4 or P-gp, others: no dose reduction necessary. Strong inducers of CYP3A4 decrease exposure by half, thus not for treatment of vital indications (PE, DVT).
[88]
Dabigatran Anticoagulation none substrate for P-gp
20% glucuronidation, 80% eliminated unchanged
[88]
Dalteparin Anticoagulation none [89, 90] Nadroparin Anticoagulation none [90, 91]
Rivaroxaban Anticoagulation CYP3A4, CYP2J2 substrate of P-gp and BCRP
CYP independent as well
Inducers of CYP3A4 diminish, inhibitors of CYP3A4 and P-gp increase exposure - interaction significant with strong inhibitors.
[88]
Unfractionated heparin
Anticoagulation none via RES [90, 92]
Warfarin Anticoagulation
CYP1A2 and CYP3A4 (R enantiomer), CYP2C9 (S enantiomer)
The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered. Competing substrates increase, inducers decrease concentration. Monitoring INR recommended.
[93]
Anticonvulsants
Clonazepam Anticonvulsant/Sedation
CYP3A
CYP P450 inducers reduce concentration by 30%, inhibitors reduce BZD clearance
[94]
Diazepam Anticonvulsant/Sedation
CYP2C19, CYP3A4/5
Inhibitors of CYP3A4 and/or CYP2C19 increase, inducers of CYP3A4 reduce plasma concentration
[95]
Lamotrigin Anticonvulsant none
(major) glucuronidation via glucuronyl transferase 1A4
[96, 97]
Levetiracetam Anticonvulsant none
enzymatic hydrolysis of the acetamide group in the blood
[98, 99]
Lorazepam Anticonvulsant/Sedation
none mainly glucuronidation
[100]
Phenytoin Anticonvulsant CYP2C9, CYP2C19
inducer CYP1A2, CYP2C19 and CYP3A
[96, 101-103]
Valproic acid Anticonvulsant (minor) CYP2C9, CYP2A6, CYP2B6
inhibitor CYP2C9, CYP2C19
glucuronidation via UGT1A6, UGT1A9, and UGT2B7 (30-40%), beta-oxydation in mitochondria
Inhibits metabolism of CYP2C9 and UGT substrates, extensively bound to plasma proteins - possible displacement.
[96, 101, 104, 105]
Antimicrobial treatment
Acyclovir antiviral (herpes viruses)
none weak inhibitor CYP1A2
substrate of OAT1, possibly OAT2
Competition for OAT1. Nephrotoxicity and myelosuppression can be enhanced.
[80, 102, 104, 106]
Amikacin Antibiotic none none None, >90% Caution with other
eliminated unchanged
nephrotoxic and ototoxic drugs due to potential for additive effects, neuromuscular blockade may be potentiated with neuromuscular blocking agents.
[104, 107]
Amoxicillin-Clavulanate
Antibiotic none none substrate of OAT3
[108, 109]
Ampicillin Antibiotic none none [104] Ampicillin-Sulbactam
Antibiotic none none
Anidulafungin Antifungal none chemical degradation
[110]
Azithromycin Antibiotic CYP3A4 (weak)
No significant influence on CYP3A4. QT prolongation, Darunavir/cobicistat could potentially increase azithromycin exposure (inhibition of P-gp and MRP2).
[111]
Aztreonam Antibiotic none none [112]
Benzylpenicillin Antibiotic none none substrate of OAT3
[80, 104]
Caspofungin Antifungal none
spontaneous degradation, peptide hydrolysis, N-Acetylation
When co-administering inducers of CYP P450, an increase in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose, should be considered in adult patients (since exposure is 30% lower with inducer co-administration)
[113]
Cefepime Antibiotic none none [114]
Cefotaxime Antibiotic none none substrate and mild inhibitor of OAT1 and
[80, 115]
OAT3 Ceftaroline Antibiotic none none [116]
Ceftazidim-avibactam
Antibiotic none none
substrate of OAT1 and OAT3 (avibactam)
none (both) [117]
Ceftazidime Antibiotic none none none [118]
Ceftolozane-tazobactam
Antibiotic none none
substrate and inhibitor of OAT1 and OAT3 (tazobactam)
tazobactam ring hydrolised
Tazobactam is a substrate and inhibitor for OAT1 and OAT3,but does not influence exposure of furosemide (as OAT1,3 substrate). Minimal potential for clinically relevant drug interactions with substrates of OAT1/3, CYP3A4, and CYP1A2.
[117, 119]
Ceftriaxone Antibiotic none none
substrate and mild inhibitor of OAT1 and OAT3
[80, 120]
Ciprofloxacin Antibiotic none inhibitor CYP1A2, CYP3A4
QT prolongation. [102, 121]
Clarithromycin Antibiotic CYP3A4 CYP3A4 inhibitor
P-gp, OATP1B1 and OATP1B3 inhibitor
Increases exposure of CYP3A4 substrates. QT prolongation.
[102, 111]
Clindamycin Antibiotic CYP3A4
Inducers of CYP P450 lower concentration, CYP P450 inhibitors increase concentration; neuromuscular blockade may be enhanced with neuromuscular blocking agents.
[122]
Colistin Antibiotic none not well Caution with other [123]
characterised nephrotoxic drugs due to potential for additive effects.
Daptomycin Antibiotic none none
80% eliminated unchanged, site of metabolism not identified
Possible enhanced nephrotoxicity with nephrotoxic agents, possible enhanced myotoxicity with statins.
[124]
Doxycycline Antibiotic none none some hepatic metabolism, but not significant
CYP P450 inducers can lower concentrations (eg. rifampicin, antiepileptics).
[125]
Ertapenem Antibiotic none none
dehydropeptidase-I-mediated hydrolysis of the beta-lactam ring
[126]
Flucloxacillin Antibiotic likely CYP3A4, but no clinical relevance
none Partly secreted by active secretion via OAT1.
[127, 128]
Fluconazole Antifungal none
inhibitor CYP3A4, CYP2C9, CYP2C19
mostly eliminated unchanged
[102, 129-131]
Gancyclovir antiviral (CMV) none Nephrotoxicity and myelosuppression can be enhanced.
[104, 132]
Gentamicin Antibiotic none none
Caution with other nephrotoxic and ototoxic drugs due to potential for additive effects, neuromuscular blockade may be potentiated with neuromuscular blocking agents.
[104, 133]
Imipenem Antibiotic none none
dehydropeptidase-I-mediated hydrolysis of the beta-lactam ring
[134]
Isovuconasole Antifungal CYP3A4/5 moderate inhibitor of CYP3A4/5,
mild Pgp inhibitor
uridine diphosphate-glucuronosyltrans
Shortening of QT interval (concentration-dependant)).
[129, 135]
mild CYP2B6 inducer
ferases
Levofloxacin Antibiotic none weak inhibitor CYP2C9
QT prolongation. [121]
Linezolid Antibiotic none none nonenzymatic oxydation
MAOI- interactions likely with other MAOI; increases hypertensive action - careful titration of vasopressors necessary (dopaminergic as well); with SSRI possible serotonin syndrome, thus contraindicated combination.
[136, 137]
Liposomal amphotericin B
Antifungal none [138]
Meropenem Antibiotic none none [139]
Metronidazole Antibiotic possibly CYP P450 inhibitor of CYP2C9
liver hydroxylation, oxidation and glucuronidation
Disulfiram-like reaction with alcohol.
[131, 140]
Micafungin Antifungal CYP3A4 (minor) arylsulfatase, catechol-O-methyltransferase,
Possible CYP3A4 inhibition, but not clinically relevant.
[141]
Moxifloxacin Antibiotic none
glucuronide via UGT1A1, UGT1A3 and UGT1A9 and sulphate conjugation
QT prolongation. [121, 142]
Oseltamivir Antiviral (influenza) none liver esterases [143]
Piperacillin-Tazobactam
Antibiotic none none
substrate and inhibitor of OAT1 and OAT3 (tazobactam)
Tazobactam is a substrate and inhibitor for OAT1 and OAT3, but does not influence exposure of furosemide (as OAT1,3 substrate). Minimal potential for clinically relevant drug
[109, 119, 144]
interactions with substrates of OAT1/3, CYP3A4, and CYP1A2.
Rifampicin Antibiotic none
inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4
inducer of P-gp and MRP2
Inducer of UGT, sulfotransferases, carboxylesterases as well.
[102, 145-147]
Tigecycline Antibiotic none none P-gp substrate not extensively metabolized
Potential interaction with P-gp inhibitors.
[148]
TMP/SMX Antibiotic CYP2C9 inhibitor CYP2C9, CYP2C8
[131]
Vancomycin Antibiotic none none None, >90% eliminated unchanged
Caution with other nephrotoxic drugs due to potential for additive effects.
[149]
Voriconazole Antifungal CYP2C19
inhibitor CYP3A4, CYP2C9, CYP2C19, CYP2B6
QT prolongation. [102, 129, 130, 150]
ARDS treatment
Atracurium/Cisatracurium
ARDS none
plasma esterases and Hoffman degradation (amide to amine)
[151]
Nitric Oxide Gas ARDS none reaction with O2, ROS and haemoglobin
[152]
Rocuronium ARDS and rapid sequence intubation
none liver esterases [151]
Immunosuppressors
Azathioprine Solid organ graft, autoimmune
none by xanthine oxidase,
Xanthine oxidase inhibitors decrease metabolism.
[104, 153, 154]
conditions thiopurine methyltransferase, and hypoxanthine phosphoribosyltransferase
Cyclosporine Solid organ graft CYP3A4 inhibitor CYP 3A4
inhibitor of P-gp, BCRP, OATP1B1 and OATP1B3
[102, 155, 156]
Everolimus Solid organ graft CYP3A4 substrate and inhibitor of P-gp
Co-administration with strong CYP3A4 or P-gp inducers or inhibitors is not recommended.
[157]
Methylprednisolone
Immunosuppressant CYP3A4
CYP3A4 inhibitors increase, inducers decrease, substrates can either increase or reduce exposure.
[158]
Mycophenolate Mofetil
Solid organ graft none inhibition of OAT1 and OAT3
glucuronidation with UGT1A9 - enterohepatic recycling to mycophenolic acid (major), and (minor) acylglucuronide formation
Drugs affecting glucuronidation of MPA may change MPA exposure.
[80, 104, 159]
Tacrolimus Solid organ graft CYP3A4 inhibitor CYP3A4
P-gp inhibitor
Inhibitors of CYP3A4 increase, inducers decrease concentration; extensively bound to plasma proteins - possible displacement, tacrolimus inhibits CYP3A4, possible enhanced neuro-and nephrotoxicity in combination with neuro-or nephrotoxic agents; ECG monitoring advised in combination with drugs which prolong QT and
[102, 104, 156, 160, 161]
CYP3A4 inhibitors.
Intubation Etomidate Intubation none none liver esterase [162]
Suxamethonium Intubation none none
pseudocholinesterase, butyrylcholinesterase
[163]
Vecuronium Intubation none none deacetylation in the liver
[151, 164]
Other cardiovascular treatments
Acetylsalicylic acid
platelet aggregation inhibitor
none substrate of OAT2
deacetylation [165]
Amiodarone Antiarrhythmic CYP3A4
inhibitor CYP1A2, CYP2C9, CYP2D6, CYP3A4
P-gp inhibitor QT prolongation. [102, 166, 167]
Atorvastatin Dyslipidemia CYP3A4
substrate of OATP1B1, OATP1B3 and P-gp
[102, 168]
Bisoprolol Beta blocker CYP3A4, CYP2D6 CYP2D6 inhibitors increase concentration.
Carvedilol Beta blocker CYP1A2, CYP2E1, CYP2C9, CYP3A4, CYP2D6
P-gp inhibitor CYP2D6 inhibitors increase concentration.
[81, 102]
Clopidogrel platelet aggregation inhibitor
CYP2C19 (main), CYP1A2, CYP2B6, CYP3A4
weak inhibitor CYP2B6, inhibitor CYP2C8 (metabolite)
esterases [169]
Digoxin Antiarrhythmic none P-gp substrate, substrate for OATP4C1
[170]
Esmolol Beta blocker none RBC esterases [171]
Furosemide Henle loop diuretic none substrate for OAT1 and OAT3
glucuronidation Electrolyte disturbances can enhance toxicity of drugs that prolong QT.
[172]
Landiolol Beta blocker none (in vitro)
hydrolysis of ester moiety by pseudocholinesterases and carboxylesterases, beta-oxydation
[173]
Levosimendan Inotropic none N-acetyl transferase-2
[174, 175]
Nicardipin Antihypertensive CYP3A4 [102, 176]
Pravastatin Dyslipidemia none substrate OATP1B3, OATP1B1
[102, 168]
Rosuvastatin Dyslipidemia
CYP2C9 (main, 10%), CYP2C19, CYP3A4 and CYP2D6
substrate of OATP1B1, OATP1B3 and BCRP
[102, 168]
Sildenafil Phosphodiesterase 5 inhibitor
CYP3A4, CYP2C9
weak inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6,
[177]
CYP2E1 and CYP3A4, but not clinically relevant
Simvastatin Dyslipidemia CYP3A4
substrate of OATP1B1, OATP1B3 and P-gp
[102, 168]
Ticagrelor platelet aggregation inhibitor
CYP3A4 mild CYP3A4 inhibitor
P-gp substrate and weak inhibitor
[178]
Uradipil Antihypertensive likely CYP P450 substrate
[179]
Verapamil Antiarrhythmic substrate CYP3A4, CYP3A5, CYP2C8, CYP2E1
CYP3A4 and CYP1A2 (weak) inhibitor
Pgp and OCT1 inhibitor
CYP3A4 inhibitors reduce clearance.
[81, 102]
Other supportive treatment
Hydrocortisone immunosuppressive (under study for COVID-19)
CYP3A4
CYP3A4 inhibitors increase, inducers decrease concentration; substrates can either increase or reduce exposure
[180]
Lansoprazole Proton-pump inhibitors
CYP2C19, CYP3A4 (minor)
in vitro inducer CYP1A2
Inducers affecting CYP2C19 and CYP3A4 reduce exposure
[102, 181, 182]
Omeprazole Proton-pump inhibitors
CYP2C19, CYP3A4
CYP2C19 inhibitor, in vitro inducer CYP1A2
CYP2C19 and CYP3A4 inducers/inhibitors can reduce/increase exposure. Esomeprazol - S-enantiomere of omeprazole with similar CYP profile.
[102, 181, 182]
Pantoprazole Proton-pump inhibitors
CYP2C19, CYP3A4
CYP2C19 and CYP3A4 inducers/inhibitors can reduce/increase exposure
[181, 182]
Sedatives
Clonidin sedative and antihypertensive
CYP2D6 (mostly), CYP1A1/2, CYP3A4/5
[183]
Dexmedetomidine sedation
CYP2A6 (mainly), CYP1A2, CYP2E1, CYP2D6, CYP2C19
In vitro inhibition of CYP2C9, CYP3A4 and CYP1A2, but due to much lower concentrations than IC50 of inhibition (10-50x lower), probably no clinical relevance probably none.
[184-186]
Haloperidol Neuroleptic CYP3A4, CYP2D6 inhibitor of CYP2D6
Inhibition of metabolic enzymes increases exposure, inducers reduce exposure. Prolongation of QT interval.
[187, 188]
Ketamine Sedation CYP3A4, CYP2B6, CYP2C9
[189]
Midazolam Sedation CYP3A4 glucuronidation CYP3A4 inhibitors increase exposure
[164]
Propofol Sedation CYP2B6, CYP2C9
weak CYP3A4 inhibitor
liver glucuronidation
CYP3A4 inhibitors reduce clearance
[164, 190]
Risperidon Neuroleptic CYP2D6, CYP3A4 P-gp substrate
P-gp inhibition increases exposure, P-gp inducers reduce exposure, inhibition of metabolic enzymes increases exposure, inducers reduce exposure. Prolongation of QT interval.
[191-193]
Treatment of pain
Alfentanil Analgesia CYP3A4 [164, 194]
Diclofenac Analgesia, antipyretic
CYP2C9 inhibition of OAT1 and OAT4
UGT2B7 glucuronidation
Strong CYP2C9 inhibitors can increase concentration, 99% bound to plasma
[80, 104, 195]
proteins, possibility of displacement.
Fentanyl Analgesia CYP3A4 CYP3A4 inhibitors can inhibit up to 90% fentanyl metabolism.
[164, 196, 197]
Morphine Analgesia none glucuronide Severe CNS excitation or depression with MAOI.
[164, 198]
Naproxen Analgesia, antipyretic
CYP2C9, CYP1A2 inhibition of OAT1 and OAT3
99% bound to plasma proteins, possibility of displacement.
[80, 199, 200]
Nefopam Analgesia likely CYP P450 substrate
glucuronidation Anticholinergic adverse effects.
[201]
Paracetamol/Acetaminophen
Analgesia, antipyretic
CYP2E1 and possibly CYP1A2 and CYP3A4
major route: conjugation to glucuronide and sulphate
[104, 202, 203]
Vasoactive drugs
Dobutamine Inotropic none none COMT, glucuronidation
Proarrhythmic. [104, 204]
Epinephrine Vasopressor/inotropic
none none MAO, COMT, sulphotransferases
Reuptake a major mechanism for terminating action. Proarrhythmic.
[104]
Norepinephrine Vasopressor none none MAO, COMT, sulphotransferases
Reuptake a major mechanism for terminating action. Proarrhythmic.
[104, 205]
Vasopressin (argipresin)
Vasopressor none none rapid enyzmatic breakdown in plasma
[206]
ACEI: ACE inhibitor; MAO: monoamine oxidase; COMT: catechol-O-methyltransferase; P-gp: P-glycoprotein; UGT: UDP-glucuronosyltransferase;
CNS: central nervous system, MAOI: monoamine oxidase inhibitor, ROS: reactive oxygen species, RES: reticuloendothelial system; OAT: organic
anion transporter, OATP: organic anion transporting polypeptides; MRP: multidrug resistance-associated protein; MPA: mycophenolic acid; BCRP:
Breast Cancer Resistance Protein; PE: pulmonary embolism; DVT: deep vein thrombosis; SSRI: selective serotonin reuptake inhibitors; INR:
international normalised ratio
Table 6. Expected PK of the antivirals used to treat COVID-19 with extracorporeal support treatments Effects on pharmacokinetic parameters Protein binding
(%) Name of antiviral RRTa ECMOb
Extracorporeal systemic inflammatory responseg
Remdesivir n.a.c n.a. n.a. n.a.
Chloroquine - likelyh Alterations in cytochrome metabolism
40-60 [15, 21]
Lopinavir - likelyh Alterations in cytochrome metabolism
98-99 [207]
Ritonavir - likelyh Alterations in cytochrome metabolism
99 [208]
Favipiravir - Increases Vde Alterations in cytochrome metabolism
54 [22]
Ribavirin - Increases Vd - 0 [16]
Arbidol (Umifenovir) - - Alterations in cytochrome metabolism
n.a.
Hydroxychloroquine - likelyh Alterations in cytochrome metabolism
40-60 [15, 21]
PegIFNf-α2β - - - n.a.
IFN-α1β - - - n.a.
IFN-α - - - n.a.
aRRT: renal replacement therapies; bECMO: extracorporeal membrane oxygenation; cn.a.: not available; dCL: clearance; eVd: volume of distribution; fIFN:
interferon, g: for example systemic inflammatory response syndrome (SIRS) caused by extracorporeal life support system (ECLS), h: sequestration of drug to
ECMO oxygenator is likely, but is unlikely to affect dosing needs
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