- 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

-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


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


Baricitinib

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

Rutgers University

Patients of COVID-19, especially those of more vulnerable groups, benefit from the application of chronic treatments often in combination. In serious cases of COVID-19 multi organ failure can result, requiring medication management of multiple drugs like benzodiazepines, anticoagulants, opioids and more. There are over 300 ongoing clinical trials for therapeutic management of COVID-19. With multiple drugs being tested and used in combination it is very likely for drug-drug interactions to occur between medications for treatment and resuscitation and other medications being taken by the patient. In addition, inflammatory effects of COVID-19 can change the pharmacokinetic behavior of drugs being taken. Ultimately it is essential to assess clinically significant drug interactions of medications taken by COVID-19 patients and patients also suffering from other medicated disease states. 

Potential drug drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments

Lemaitre, F., Solas, C., Grégoire, M., Lagarce, L., Elens, L., Polard, E., . . . Barin‐Le Guellec, C. (2020). Potential drug–drug interactions associated with drugs currently proposed for COVID‐19 treatment in patients receiving other treatments. Fundamental & Clinical Pharmacology, 34(5), 530-547. doi:10.1111/fcp.12586

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments

Analyzing a drug's pharmacokinetic interactions is essential for predicting risks associated with certain medications. This can be predicted through dedicated interaction studies, clinical case reports, and in vitro to in vivo extrapolation (IVIVE) which uses in vitro experimental data to predict effects in vivo. Pharmacodynamics is also an important factor in drug interactions. This involves knowing and understanding the mechanisms of actions and safety profiles of co administered drugs and their additive or antagonistic properties. 

Risk Assessment and Possible Strategies to Minimize Drug-Drug interactions

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

- antipyretics and analgesics
- drugs in cardiovascular diseases
- drugs in infectious diseases
- anti cancer drugs
- drugs in transplantation and autoimmune diseases
- drugs in neuropsychiatric diseases
- drugs in respiratory diseases

Assessment and Management of the Risk of Drug-Drug Interactions with Other Widely Used Drugs

- Pharmacokinetics: What the body does to the drug (Absorption, Distribution, Metabolism, Elimination)

- Pharmacodynamics: What the drug does to the body 

- Antipyretics: fever relieving drugs

- Analgesics: pain relieving drugs

- NSAIDs: Nonsteroidal Anti Inflammatory Drugs; used to reduce pain, fever, prevent clots, and sometimes decrease inflammation

- DOACs: Direct Oral Anticoagulants; generally block a single blood clotting factor to treat or prevent clots (use in deep vein thrombosis, thromboembolism, etc.)

- OAT: Organic Anion Transporters; uptake transporters; substrates are generally multi ringed and negatively charged

- OATP: Organic Anion Transporting Polypeptides; uptake transporters; substrates generally have ring structures and are negatively charged

- OCT: Organic Cation Transporters; uptake transporters; substrates are generally small, simple and positively charged

- P-gp (MDR1): P glycoprotein transporter; efflux transporter; reduced oral absorption and mediates bile and urine excretion; substrates are generally cationic and amphiphilic (having hydrophobic and hydrophilic properties) compounds and some can be very large

- STAT: Signal Transducers and Activators of Transcription; regulate immune function and new blood vessel formation (angiogenesis) via interactions with DNA upon activation 

- JAK: Janus Kinases; activated by the binding of cytokines, phosphorylate other JAKs and other proteins like STATs

- m-TOR: Mechanistic target of rapamycin; major regulator of cell growth (i.e. muscle growth) and controls many catabolic and anabolic process that occur in response to nutrients and nutrient signals; it has a key regulatory function in cardiovascular physiology

- CYP: Cytochrome P450; enzyme superfamily important in the metabolism of various compounds for clearance from the body; mainly found in the liver 

- QT prolongation: electrical rhythm disturbance of the heart; delayed repolarization of the heart ventricles so the heart takes longer to recharge between beats; potential to cause fast and abnormal heart beats 

- Torsades de Pointes: lethal heart rhythm disturbance; the ventricles (lower heart chambers) beat fast and out of sync with the atria (upper heart chambers); can be triggered by QT prolongation and can cause ventricular fibrillation and cardiac arrest

- Bradycardia: slow heart rate

- *Increased drug exposure: increased concentration of drug in the body which leads to a higher chance of drug toxicity; this can be due to numerous factors like decreased drug clearance 

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