Crushing lopinavir/ritonavir tablets does not result in lower exposure to lopinavir/ritonavir in adult patients with COVID-19.

OBJECTIVE: Lopinavir/ritonavir (LPV/RTV) exposure is decreased in children after crushing the tablets. Whether exposure is also decreased in adult patients is not known. This study evaluated the exposure of LPV/RTV in adult patients after administration of crushed LPV/RTV tablets. METHODS: Blood samples were drawn from patients with COVID-19 who were receiving crushed LPV/RTV 400/100 mg tablets twice daily. RESULTS: Plasma concentrations for 11 patients with COVID-19 (eight men, mean age 62.6 years) were included. The measured plasma concentrations of LPV were substantially higher than reported for patients with HIV. CONCLUSIONS: There is adequate exposure from crushed LPV/RTV tablets, but because of limited experience, therapeutic drug monitoring is still advised.

Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications.

The coronavirus disease 2019 (COVID-19) antiviral nirmatrelvir/ritonavir (Paxlovid) has been granted authorization or approval in several countries for the treatment of patients with mild to moderate COVID-19 at high risk of progression to severe disease and with no requirement for supplemental oxygen. Nirmatrelvir/ritonavir will be primarily administered outside the hospital setting as a 5-day course oral treatment. The ritonavir component boosts plasma concentrations of nirmatrelvir through the potent and rapid inhibition of the key drug-metabolizing enzyme cytochrome P450 (CYP) 3A4. Thus nirmatrelvir/ritonavir, even given as a short treatment course, has a high potential to cause harm from drug-drug interactions (DDIs) with other drugs metabolized through this pathway. Options for mitigating risk from DDIs with nirmatrelvir/ritonavir are limited due to the clinical illness, the short window for intervention, and the related difficulty of implementing clinical monitoring or dosage adjustment of the comedication. Pragmatic options are largely confined to preemptive or symptom-driven pausing of the comedication or managing any additional risk through counseling. This review summarizes the effects of ritonavir on drug disposition (i.e., metabolizing enzymes and transporters) and discusses factors determining the likelihood of having a clinically significant DDI. Furthermore, it provides a comprehensive list of comedications likely to be used in COVID-19 patients which are categorized according to their potential DDI risk with nirmatrelvir/ritonavir. It also discusses recommendations for the management of DDIs which balance the risk of harm from DDIs with a short course of ritonavir, against unnecessary denial of nirmatrelvir/ritonavir treatment.

Dexamethasone is a dose-dependent perpetrator of drug-drug interactions: implications for use in people living with HIV.

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug-drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations.

Drug-induced Liver Injury in a Patient With Coronavirus Disease 2019: Potential Interaction of Remdesivir With P-Glycoprotein Inhibitors.

We report a case of a man with COVID-19 who developed acute hepatotoxicity related to remdesivir with probable interaction of P-glycoprotein (P-gp) inhibitors. Until further details on this interaction become available, we recommend physicians to be cautious with the prescription of P-gp inhibitors in patients receiving remdesivir therapy.

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment.

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.

Antibody Profiling of COVID-19 Patients in an Urban Low-Incidence Region in Northern Germany.

A vast majority of COVID-19 cases present with mild or moderate symptoms. The study region is in an urban and well-defined environment in a low-incidence region in Northern Germany. In the present study, we explored the dynamics of the antibody response with respect to onset, level and duration in patients with confirmed SARS-CoV-2 infection. Anti-SARS-CoV-2 IgG and IgA were detected by automated enzyme-linked immunosorbent assay (ELISA) of SARS-CoV-2 infected patients monitored by the Health Protection Authority. This explorative monocentric study shows IgA and IgG antibody profiles from 118 patients with self-reported mild to moderate, or no COVID-19 related symptoms after laboratory-confirmed infection with SARS-CoV-2. We found that 21.7% and 18.1% of patients were seronegative for IgA or IgG, respectively. Clinically, most of the seronegative patients showed no to only moderate symptoms. With regard to antibody profiling 82% of all patients developed sustainable antibodies (IgG) and 78% (IgA) 3 weeks or later after the infection. Our data indicate that antibody-positivity is a useful indicator of a previous SARS-CoV-2 infection. Negative antibodies do not rule out SARS-CoV-2 infection. Future studies are needed to determine the functionality of the antibodies in terms of neutralization capacity leading to personal protection and prevention ability to transmit the virus as well as to protect after vaccination.

Drug interactions: a review of the unseen danger of experimental COVID-19 therapies.

As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug-drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for 'COVID-19', '2019-nCoV', '2019 novel coronavirus' and 'SARS-CoV-2'. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms 'COVID-19', 'Comorbidity' and 'Epidemiological Factors'. Potential drug-drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug-drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug-drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug-drug interaction resource to facilitate medication review for the critically ill patient.

SARS-CoV-2 and HIV protease inhibitors: why lopinavir/ritonavir will not work for COVID-19 infection.

Since the beginning of the outbreak of severe acute respiratory syndrome (SARS) coronavirus (CoV) 2, lopinavir/ritonavir was selected for treatment. The recent publication of Cao et al. in the New England Journal of Medicine showed that lopinavir/ritonavir treatment did not accelerate clinical improvement compared with standard of care. This raised the question of whether in retrospect we could have known this. The aim of this paper is to gather all the available evidence and to comprehensively discuss this issue.