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\begin{document}

\title{COVID-19 treatment in patients with comorbidities: Awareness of
drug-drug interactions.}



\author[1]{David Back}%
\author[2]{Catia Marzolini}%
\author[2]{Catherine Hodge}%
\author[1]{Fiona Marra}%
\author[2]{Alison Boyle}%
\author[1]{Sara Gibbons}%
\author[3]{David M. Burger}%
\author[1]{Saye Khoo}%
\affil[1]{University of Liverpool Faculty of Health and Life Sciences}%
\affil[2]{Affiliation not available}%
\affil[3]{Radboud university medical center}%


\vspace{-1em}



  
  \date{March 15, 2025}


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\begin{abstract}
In a recent issue of Br J Clin Pharmacol Smith et al1 published an
outstanding commentary titled `Dosing will be a key success factor in
repurposing antivirals for Covid-19'. They highlighted that the success
in our repurposing efforts will be dependent on `getting the dose right'
for drugs which have been developed for different indications and
stressed some of the unique challenges of treating this particular
disease. They pointed the reader to lopinavir/ritonavir (LPV/r) as an
example of a repurposed antiviral and the limited experience of this
drug regimen (and other treatments) in the elderly population with
comorbidities -- ie those most at risk from Covid-19. It is on the issue
of comorbidities, polypharmacy and drug-drug interactions (DDIs) that we
wish to comment.%
\end{abstract}%



\sloppy


\textbf{COVID-19 treatment in patients with comorbidities: Awareness of
drug-drug interactions.}

David Back\textsuperscript{1}*, Catia Marzolini\textsuperscript{1,2,3},
Catherine Hodge\textsuperscript{1}, Fiona Marra\textsuperscript{4},
Alison Boyle\textsuperscript{4}, Sara Gibbons\textsuperscript{1}, David
Burger\textsuperscript{5} \& Saye Khoo\textsuperscript{1,6}.

\textsuperscript{1}Department of Molecular and Clinical Pharmacology,
Institute of Translational Medicine, University of Liverpool, Liverpool,
UK

\textsuperscript{2}Division of Infectious Diseases and Hospital
Epidemiology, Departments of Medicine and Clinical Research, University
Hospital of Basel, Basel, Switzerland

\textsuperscript{3}University of Basel, Basel, Switzerland

\textsuperscript{4}Department of Pharmacy, NHS Greater Glasgow and
Clyde, Glasgow, UK.

\textsuperscript{5}Radboud University Medical Centre, Nijmegen, the
Netherlands.

\textsuperscript{6}Royal Liverpool University Hospital, Liverpool UK

*e.mail: daveback@liverpool.ac.uk

Arising from: Smith PF et al Br J Clin Pharmacol 2020; Apr 17. doi:
10.1111/bcp.14314

In a recent issue of Br J Clin Pharmacol Smith et
al\textsuperscript{1}published an outstanding commentary titled `Dosing
will be a key success factor in repurposing antivirals for Covid-19'.
They highlighted that the success in our repurposing efforts will be
dependent on `getting the dose right' for drugs which have been
developed for different indications and stressed some of the unique
challenges of treating this particular disease. They pointed the reader
to lopinavir/ritonavir (LPV/r) as an example of a repurposed antiviral
and the limited experience of this drug regimen (and other treatments)
in the elderly population with comorbidities -- ie those most at risk
from Covid-19. It is on the issue of comorbidities, polypharmacy and
drug-drug interactions (DDIs) that we wish to comment.

Age-related comorbidities result in complex polypharmacy and an
increased risk of DDIs\textsuperscript{2}. Furthermore, physiological
changes related to ageing may affect both pharmacokinetics (PK) and
pharmacodynamics (PD) thereby putting elderly patients at risk of
inappropriate prescribing and adverse drug reactions. In the case of
LPV/r, particular attention needs to be focussed on PK interactions
involving inhibition of CYP3A4 and some transporters\textsuperscript{2}.
To aid health care professionals managing LPV/r (and other
antiretroviral) DDIs in HIV patients we developed the online resource
www.hiv-druginteractions.org\textsuperscript{3}which is extensively
cited in national and international treatment guidelines. However, in
addition to PK interactions, LPV/r is known to cause QT prolongation and
is on the CredibleMeds listing\textsuperscript{4} for drugs with a
possible risk of torsades de pointes (TdP). Indeed the drug label for
LPV/r includes the warning to `avoid use with QT-prolonging drugs'
because of DDIs and effects on PR and QTc\textsuperscript{5}.

Possibly of greater topicality at present is the risk of QT prolongation
and TdP in Covid-19 patients given the repurposed drugs chloroquine and
hydroxychloroquine. This has been highlighted in recent cohort
studies\textsuperscript{6,7} and in warnings from the
EMEA\textsuperscript{8} and FDA\textsuperscript{9}.

Patients given experimental COVID-19 therapies will often be clinically
unstable with organ dysfunction, and the development of toxicities from
DDIs must be carefully considered. These very ill patients may not only
be receiving an experimental COVID drug with a known or possible risk of
TdP as single agents or combined (LPV/r, chloroquine,
hydroxychloroquine, azithromycin)\textsuperscript{4} but can have other
risk factors for TdP such as hypokalemia, female gender, age
\textgreater{} 70 years as well as concomitant (eg some anaesthetics,
muscle relaxants, analgesics, antiarrhythmics, antibacterials,
antipsychotics, gastrointestinal agents) thereby potentially increasing
the risk of TdP\textsuperscript{10}. The CredibleMeds website classifies
drugs into those with a known risk, a possible risk and a conditional
risk of TdP. However, there is still the challenge of giving appropriate
clinical advice to guide the safe use of a COVID therapy and one or more
co-medications in individual patients. Having established prescribing
resources for managing DDIs in other viral infections (with a database
of commentaries on \textgreater{}30,000 DDIs, with data systematically
collected from medical and scientific literature, information from drug
regulatory authorities or expert opinion), to meet the challenge of the
COVID pandemic a similar resource is now available at
www.covid19-druginteractions.org\textsuperscript{11}. DDIs are graded
into four levels and colour coded: i) no clinically significant
interaction expected (green); ii) potential interaction likely of weak
relevance (yellow); iii) potential interaction that may require close
monitoring, alteration of drug dosage or timing of administration
(amber); and iv) drugs should not be co-administered (red). It is made
clear that the decision to give or not give drugs is always the
responsibility of the prescriber with many other factors having to be
considered such as age and electrolyte imbalance. In addition since
chloroquine and hydroxychloroquine have very long half-lives (30-60
days) DDIs may occur even after discontinuing
treatment\textsuperscript{9}. Systematic medication review should aim at
discontinuing unnecessary QT prolonging drugs or finding alternatives
devoid of QT risk. The use of decision support systems is important in
effective management of drug therapies in COVID patients.

\textbf{Author Contributions}

DBa, CM, CH, FM, AB, SG, DBu, SK, have all been involved in the
development of the web resource www.covid19-druginteractions.org. Dba,
CM and DBu wrote this manuscript.

\textbf{Competing Interests.}

DBa, SK received educational grant funding for
www.covid19-druginteractions.org from Novartis and Abbvie.

\textbf{References}

1. Smith PF, Dodds M, Bentley D, Yeo K. Dosing will be a key success
factor in repurposing antivirals for COVID-19. Br J Clin Pharmacol 2020;
Apr 17. doi: 10.1111/bcp.14314.

2. Back DJ \& Marzolini C. The challenge of HIV treatment in an era of
polypharmacy. J Int AIDS Soc. 2020; 23, e25449.

3. http://www.hiv-druginteractions.org (2020). Accessed April
28\textsuperscript{th} 2020

4. http://www.CredibleMeds.org (2020). Accessed April
28\textsuperscript{th} 2020.

5. Kaletra\selectlanguage{ngerman}® prescribing information (April 2020). Accessed April
28\textsuperscript{th} 2020

6. Borba MGS, Val FFA, Sampaio VS et al. Effect of high vs low dose
chloroquine diphosphate as adjunctive therapy for patients hospitalised
with severe respiratory syndrome coronavirus 2 (Sars-Cov-2) infection: A
randomised clinical trial. JAMA Netw Open 2020; April 1: 3 (4) e208857.

7. Chorin E, Dai M, Shulman E et al. The QT interval in patients with
COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med 2020;
https://doi.org/10.1038/s41591-020-0888-2.

8. EMEA news release April 23\textsuperscript{rd} 2020.
http://www.ema.europa.eu.

9. FDA drug safety communication. April 24\textsuperscript{th} 2020.
http://www.fda.gov/safety

10. http://www.medsafetyscan.org. Accessed April 28\textsuperscript{th}
2020.

11. http://www.covid19-druginteractions.org. Accessed April
28\textsuperscript{th} 2020.

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