1
In a recent issue of Br J Clin Pharmacol, Smith et al.
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—that is, 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.
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.
2
To aid health care professionals managing LPV/r (and other antiretroviral) DDIs in
HIV patients, we developed the online resource http://www.hiv-druginteractions.org,
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
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.
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
6
,
7
and in warnings from the EMEA
8
and FDA.
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, and azithromycin)
4
but can have other risk factors for TdP such as hypokalaemia, female gender, age >
70 years, and concomitant (e.g., some anaesthetics, muscle relaxants, analgesics,
antiarrhythmics, antibacterials, antipsychotics, and gastrointestinal agents) thereby
potentially increasing the risk of TdP.
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 >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 http://www.covid19-druginteractions.org.
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.
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.
2
COMPETING INTERESTS
D.Ba. and S.K. received educational grant funding for http://www.covid19-druginteractions.org
from Novartis and Abbvie.
CONTRIBUTORS
D.Ba., C.M., C.H., F.M., A.B., S.G., D.Bu., and S.K. have all been involved in the
development of the web resource http://www.covid19-druginteractions.org. D.Ba., C.M.,
and D.Bu. wrote this manuscript.