COVID-19 treatment in patients with comorbidities: Awareness of
drug-drug interactions.
David Back1*, Catia Marzolini1,2,3,
Catherine Hodge1, Fiona Marra4,
Alison Boyle4, Sara Gibbons1, David
Burger5 & Saye Khoo1,6.
1Department of Molecular and Clinical Pharmacology,
Institute of Translational Medicine, University of Liverpool, Liverpool,
UK
2Division of Infectious Diseases and Hospital
Epidemiology, Departments of Medicine and Clinical Research, University
Hospital of Basel, Basel, Switzerland
3University of Basel, Basel, Switzerland
4Department of Pharmacy, NHS Greater Glasgow and
Clyde, Glasgow, UK.
5Radboud University Medical Centre, Nijmegen, the
Netherlands.
6Royal 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 al1published 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 DDIs2. 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 transporters2.
To aid health care professionals managing LPV/r (and other
antiretroviral) DDIs in HIV patients we developed the online resource
www.hiv-druginteractions.org3which 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
listing4 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 QTc5.
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
studies6,7 and in warnings from the
EMEA8 and FDA9.
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)4 but can have other
risk factors for TdP such as hypokalemia, female gender, age
> 70 years as well as concomitant (eg some anaesthetics,
muscle relaxants, analgesics, antiarrhythmics, antibacterials,
antipsychotics, gastrointestinal agents) thereby potentially increasing
the risk of TdP10. 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 >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.org11. 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
treatment9. 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.