Discussion
Infection control measures and supportive cares are currently the main
clinical management for COVID-19. However, some medications are being
used based on the results of laboratory, animal and clinical studies
[7]. The current study is the first to retrospectively identify
severity, frequency, mechanism, and clinical management of pDDIs in
hospitalized patients with COVID-19. We found that 37.9% of COVID-19
patients were exposed to at least one major or contraindicated pDDI
during 24-48 h of hospital admission. More than half of pDDIs were
occurred between lopinavir/ritonavir (branded as Kaletra or Aluvia) and
medications metabolized by CYP3A4. Additive interactions between
antiplatelets/nonsteroidal anti-inflammatory drugs (NSAIDs) and
anticoagulants were the second common pDDI in COVID-19 patients.
Lopinavir, a protease inhibitor, is widely used for the treatment of
HIV. It is combined with ritonavir, another protease inhibitor, which
inhibits CYP3A4 enzyme and increases the half-life of lopinavir
[14].
Lopinavir/ritonavir
has activity against severe acute respiratory syndrome coronavirus
(SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV)
both in vitro and in animal models [15, 16]. Recently, an
open-label, randomized, phase 2 trial revealed efficacy and safety of
lopinavir/ritonavir combined with interferon beta-1b and ribavirin in
the treatment of hospitalized patients with COVID-19 [17]. Both
lopinavir and
ritonavir have important DDIs due to inhibition of CYP3A4. It is
essential to identify commonly used medications in patients with
COVID-19 which are metabolized with this enzyme and may have severe
interactions with
lopinavir/ritonavir.
Our results show that HMG-CoA reductase inhibitors (atorvastatin,
rosuvastatin) are the most frequent interacting medications with
lopinavir/ritonavir in
our patients. Some studies showed that co-administration of different
protease inhibitors with atorvastatin increased the area under the
concentration-time curve (AUC) of atorvastatin from 1.7 to 9.4 folds
(depending on the type of protease inhibitor). Reducing atorvastatin
dose to 20 mg/day and monitoring for signs and symptoms of its toxicity
(myalgia, rhabdomyolysis, liver function test (LFT) abnormalities)
should be taken into account when a protease inhibitor is used
concomitantly [18]. However, differentiation between signs and
symptoms of HMG-CoA reductase inhibitors toxicity and COVID-19 is
challenging because myalgia and abnormal LFT can also be seen in
patients with COVID-19 [9, 19]. Rosuvastatin also have the same
interaction with protease inhibitors and its dose should not be exceeded
than 10 mg/day when co-administered with lopinavir/ritonavir [20].
Rhabdomyolysis is a serious consequence of this interaction which was
reported in patients who received lopinavir/ritonavir with atorvastatin
or rosuvastatin [21, 22].
Anxiolytic/hypnotic/sedative agents such as alprazolam, chlordiazpoxide
and midazolam were administered in our patients. According to the
Lexi-Interact database, interaction of alprazolam or midazolam with
lopinavir/ritonavir is rated as good and excellent; respectively, in
terms of reliability. Other benzodiazpine agents that are less expected
to interact with protease inhibitors (e.g. lorazepam, oxazepam,
temazepam) can be administered instead of alprazolam [23]. Severe
prolonged sedation and increased length of hospital stay were reported
among patients receiving a combination of a protease inhibitor and
intravenous midazolam [24]. Therefore, this interaction is
categorized as contraindicated in terms of severity rating
[25]. However, clinical outcomes of HIV patients (on protease
inhibitors regimen) who received intravenous midazolam for procedural
sedation and those who received diazepam were similar [26]. This
combination should be administered with caution and reduced doses of
intravenous midazolam should be considered [25].
SARS-CoV-2 may affect cardiovascular system and lead to myocardial
injury, acute heart failure, or worsening pre-existing cardiovascular
disease [27]. Therefore, interaction of cardiovascular agents with
investigational medications for COVID-19 should be mentioned. In the
current study, nondihydropyridine calcium channel blockers (diltiazem),
cardiac glycosides (digoxin), antiarrhythmic agents (amiodarone,
lidocaine), and isosorbide dinitrate had major or contraindicated
interactions with lopinavir/ritonavir. Metabolism inhibition of
nondihydropyridine calcium channel blockers can lead to increase their
serum concentration and the risk of AV nodal blockade. Monitoring the
toxicity of calcium channel blockers and a 50% dose reduction of
diltiazem may be required [28]. The mechanism of major interaction
between lopinavir/ritonavir and digoxin is probably due to inhibition of
P-glycoprotein transporter and reduction of digoxin renal clearance by
ritonavir [29]. Reducing digoxin dose (30% to 50%) or dosing
frequency as well as monitoring digoxin levels is recommended [30].
Lopinavir/ritonavir may enhance the serum concentration of amiodarone
and subsequently its QTc-prolonging effect. This combination should be
avoided when possible, if not, a dose reduction and serial ECG
monitoring is recommended [31]. Combination of amiodarone and
azithromycin should also be cautioned in COVID-19 patients due to QTc
prolongation synergism effect. Our previous study showed that DDIs are
risk factor for prolonging QTc in ICU admitted patients [32].
Nevertheless, the interaction between hydroxychloroquine and
azithromycin, two medications with QTc prolongation effect
co-administered in some COVID-19 patients, is graded as minor (B)
interaction [33]. For B interactions, no intervention is needed
according to the Lexi-Interact database but calculating the risk score
of QTc prolongation before administration of this combination to
COVID-19 patients is a wisely measure.
Excessive inflammation, platelet activation, endothelial dysfunction,
and stasis may lead to arterial and venous thrombotic disease in
COVID-19 patients [34]. Drug interactions of common anticoagulants
should be considered in these patients. In the current study apixaban
and rivaroxaban were administered to the patients. Among novel oral
anticoagulants (NOACs), apixaban and rivaroxaban are substrates for both
P-glycoprotein transporter and CYP3A4. Therefore, concomitant
administration with inhibitors of CYP3A4 and P-glycoprotein transporter
(e.g. lopinavir/ritonavir) should be avoided due to increased serum
concentration of apixaban and rivaroxaban and risk of bleeding [35].
Additionally, co-administration of antiplatelets or NSAIDs with
anticoagulants may increase the risk of bleeding [36]. Because of
underlying cardiovascular diseases in some COVID-19 patients, they may
regularly use antiplatelet agents. NSAIDs may also be prescribed to
relieve myalgia [37] or for their probable effect on SARS-CoV-2
(specifically indomethacin) [38]. Anticoagulants side effects should
be monitored in COVID-19 patients receiving these combinations.
Administration of salmeterol or combination medications containing
salmeterol may be indicated in COVID-19 patients with underlying chronic
respiratory diseases. Lopinavir/ritonavir increases serum concentration
of salmeterol [39] and may predispose patients to cardiovascular
adverse effects of beta2-agonists.
Another important interaction that may occur in COVID-19 male patients
with older age is between tamsulosin and lopinavir/ritonavir. Although
the adverse consequences of this interaction has not been evaluated in
the clinical studies, this combination is contraindicated according to
the tamsulosin drug label [40]. When the combination must be used,
monitoring tamsulosin adverse effects (particularly orthostatic
hypotension) is recommended.
Logistic regression analysis confirmed that two comorbidities (IHD and
CRDs) and ICU admission were significantly associated with occurrence of
major and contraindicated pDDIs. Patients with IHD or CRDs may receive
some medications which have severe interactions with investigational
drugs for COVID-19 especially protease inhibitors. The current study
shows other investigational medications including hydroxychloroquine,
ribavirin, remdesivir, favipiravir, interferon beta or intravenous
immunoglobulin do not interact with commonly used medications for
comorbidities. Therefore, these medicines are much safer than protease
inhibitors in terms of severe DDIs. We also found critically ill
patients are more prone to DDIs because they have complicated conditions
and receive more medications.
The first limitation of the current study is that it cannot predict the
occurrence rate of actual DDIs. Because subjective and objective
evidence for an actual DDI usually are not accurately recorded
specifically during a critical pandemic condition and it is a limitation
of the retrospective studies. These evidence can be collected with a
prospective study in order to report actual DDIs. The second limitation
is using one drug interaction database. Evaluating severity rating of
some pDDIs with another drug interaction database (except Lexi-Interact)
showed a little variation. It would be better to check the interactions
with more than one database in order to report more accurate results.