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  International Workshop on
Clinical Pharmacology of HIV,
Hepatitis and Other Antiviral Drugs,
September 20-22, 2021
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Drug-Drug Interaction Risk High With COVID Meds in Hospital
  International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Four in 5 people admitted to the hospital with COVID-19 had at least one potential interaction between a COVID-19 drug and a comedication, according to a 141-person Canadian analysis [1]. The two COVID drugs most often implicated in potential interactions were lopinavir/ritonavir and hydroxychloroquine (drugs not currently recommended for COVID-19) in this study using the Liverpool-COVID and Lexicomp drug-interaction websites.
Information on interactions between drugs used to treat COVID-19 and other medications remains limited because of the novelty of the pandemic and inconsistent collection of interaction data. But such drug-drug interactions can be expected in COVID-19 patients admitted to the hospital, McGill University researchers noted, because many of these people have comorbidities and already take several drugs.
With coworkers at other Canadian centers, a McGill team conducted this study to assess prevalence of drug-drug interactions involving COVID-19 drugs and to compare the consistency of two drug-interaction websites, the Liverpool COVID site [2] and Lexicomp [3]. The primary outcome was prevalence of 1 or more potentially significant (red or amber) COVID-related drug-drug interactions in hospitalized people screened for the Canadian Treatments for COVID-19 (CATCO) study. A red warning means do not coadminister two drugs, amber signals a potential interaction, and green indicates no interaction. Equivalent severity gradings in Lexicomp are A and B for green, C and D for amber, and X for red.
CATCO is the Canadian arm of the SOLIDARITY trial [4]. COVID medications assessed were those used in SOLIDARITY [4] and the RECOVERY trial [5]: lopinavir/ritonavir, remdesivir, dexamethasone, hydroxychloroquine, azithromycin, interferon beta-1a, and tocilizumab (an IL-6 inhibitor). CATCO recruitment began in April 2020.
This multicenter, retrospective, observational analysis included 141 people screened between April 1 and September 15, 2020, 57% of them men, with a median age of 72 (interquartile range [IQR] 57 to 83). These people were taking a median of 11 comedications (IQR 7 to 14.5) for a median of 4.5 (IQR 2 to 7) comorbidities. Tisdale risk score indicated that 46.8% of participants had a moderate risk of QTc prolongation (which can lead to sudden cardiac death) and 9.2% had a high risk.
Lexicomp turned up a potential drug-drug interaction in 79.4% of study participants. COVID medications with the highest rates of potential drug-drug interactions were lopinavir/ritonavir (92.9%, 95% confidence interval [CI] 87.3 to 96.5), hydroxychloroquine (86.5%, 95% CI 79.8 to 91.7), azithromycin (76.6%, 95% CI 68.7 to 83.3), dexamethasone (72.3%, 95% CI 64.2 to 79.5), and tocilizumab (72.3%, 95% CI 64.2 to 79.5). Potential drug-drug interaction prevalence stood at only 3.5% (95% CI 1.2 to 8.1) for remdesivir and the same for interferon beta-1a.
Each person taking lopinavir had a median of 4 (IQR 2 to 6) amber or red drug-drug interactions. Median amber or red interactions were 2 (IQR 1 to 4) for hydroxychloroquine, 2 (IQR 1 to 3) for azithromycin, 1 for dexamethasone and tocilizumab, and 0 for remdesivir and interferon beta-1a.
The most-predicted drug-drug interaction outcomes were QTc prolongation (with azithromycin [22.1%] and hydroxychloroquine [18.2%]); higher risk of comedication toxicity (with lopinavir [27.1%] and dexamethasone [11.0%]); and possible drop in comedication efficacy (with tocilizumab [17.3%] and dexamethasone [10.3%]). For red drug-drug interactions, the comedications most implicated with lopinavir/ritonavir were anticoagulants (33.3%), antipsychotics (23.3%), and corticosteroids (18.3%). With hydroxychloroquine the most implicated comeds were antipsychotics and antidepressants (both 37.5%).
Multivariate logistic regression determined that each additional comedication taken doubled the odds of a drug-drug interaction involving lopinavir/ritonavir (adjusted odds ratio [aOR] 2.17, 95% CI 1.23 to 3.81, P = 0.007) or hydroxychloroquine (aOR 2.19, 95% CI 1.45 to 3.0, P < 0.001). Number of comeds also independently boosted odds of interactions with azithromycin (aOR 1.29, 95% CI 1.14 to 1.47, P < 0.001), dexamethasone (aOR 1.51, 95% CI 1.28 to 1.78, P < 0.001), and tocilizumab (aOR 1.32, 95% CI 1.17 to 1.49, P < 0.001). Respiratory disease independently upped odds of interactions with hydroxychloroquine 27-fold, while cardiovascular disease inflated odds of interactions with azithromycin 5-fold.
Concordance between Liverpool and Lexicomp was low on clinical severity of interactions (40.6%) and moderate on clinical impact of interactions (55.0%). The two web-based interaction finders were hardly comprehensive: The Liverpool-COVID database had no drug-drug interaction data for 31% of potential COVID drug-comedication combinations, while Lexicomp had no interaction data for 85% of potential COVID drug-comedication combinations. Overall, the McGill team concluded, the Liverpool COVID-19 website "was a more powerful tool to identify drug-drug interactions" involving COVID medications and comedications.
The researchers recommended routine drug-drug interaction screening and monitoring with the Liverpool COVID database [2] and pharmacy consultations for people with COVID-19. Among COVID drugs not included in this analysis, they suggested that 3 may have high risk of drug-drug interactions with comedications (colchicine, ivermectin, and ruxolitinib), while other agents may have a lower interaction risk (molnupiravir, anakinra, and barictinib).
1. Sheehan N, Tseng A, Hewlett K, et al. Drug-drug interactions in hospitalized COVID-19 patients receiving investigational drugs (CATCO-DDI). International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 3.
2. University of Liverpool. COVID-19 Drug Interactions. https://www.covid19-druginteractions.org/
3. Lexicomp. https://online.lexi.com/lco/action/home
4. ClinicalTrials.gov. Canadian arm of the SOLIDARITY trial. ClinicalTrials.gov identifier NCT04330690. https://clinicaltrials.gov/ct2/show/NCT04330690
5. RECOVERY. Randomized Evaluation of COVID-19 Therapy. https://www.recoverytrial.net/