-Prodrugs that act as false substrates during viral transcription for chain termination

Favipiravir:
- Hepatic metabolism
- Renal elimination
- CYP2C8 inhibitor
- Monitoring necessary in combination with QT prolonging drugs 


Remdesivir:
- Substrate and inducer of several CYPs and transporters
- Rapidly metabolized, low plasma exposure
- Few significant interactions expected
- Use in combination of strong enzyme inducers not recommended


Rutgers University

Drugs being used or tested:
- Hydroxychloroquine
- Viral RNA polymerase inhibitors: favipiravir and remdesivir
- HIV protease inhibitors: lopinavir/r
- Interferon beta-1b
-IL-6 inhibitors: tocilizumab and sarilumab
- Anakinra
- Azithromycin
- Baricitinib

Relevant Pharmacokinetic and Pharmacodynamic Elements about Drugs Currently Proposed for COVID-19 Treatment

- Mechanism is poorly understood
- May inhibit pH dependent entry of certain viruses into host cells or block replication of viruses by glycosylation inhibition of envelope proteins
- Anti inflammatory and immunomodulatory activities
- Can increase QT interval
- Hypoglycemic effects in non diabetic patients
- Accumulates in blood cells
- High volume of distribution (extensive tissue penetration)

Hydroxychloroquine

Viral RNA polymerase inhibitors: favipiravir and remdesivir

- HIV-1 and 2 protease inhibitor
- Significant CYP-dependent first past liver metabolism
- Substrates and inhibitors of CYP3A4 and P glycoprotein and BCRP and OATP1B1 transporters
- Responsible for many drug interactions
- Can increase the exposure and toxicity of other drugs
- Use with extreme caution in patients on multiple medications


HIV protease inhibitors: lopinavir/r

- Shown to decrease time needed to achieve a negative nasopharyngeal swab in combination with lopinavir/ritonavir and ribavirin when treating COVID-19
- Low potential for drug-drug interactions due to limited CYP interactions

Interferon beta-1b

- Bind and inhibit receptors for IL-6
- Indicated for rheumatoid arthritis and serve cytokine storm induced by CAR-T cells
- Could restore activity of CYP1A2, 2C9, 2C19, and 3A4 which are reduced by cytokine like IL-6


IL-6 inhibitors: tocilizumab and sarilumab

- IL-1 alpha and beta competitive inhibitors
- Indicated for inflammatory diseases and could act as symptomatic treatment of COVID-19
- May restore CYP mediated metabolism of drugs reduced by IL-1 during inflammation


Anakinra

- Used to cover the risk of secondary bacterial infection in COVID-19 patients
- High tissue affinity and accumulation in phagocytes
- Can increase QT prolongation
- Using in combination with other QT prolonging drugs can increase the risk of cardiac death


Azithromycin

- JAK1 and 2 inhibitor
- Decreases inflammation via inhibition of IL-6 induced STAT3 phosphorylation
- Inhibitor of OCT1 and substrate of OAT3 and apart from these interactions no clinical drug interactions are expected


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