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.

Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug-drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1-4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug-drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.