- Anticancer treatment must be suspended for patients with COVID-19 in ICU
- Highly cytotoxic chemotherapy should be avoided in COVID-19 infection
- Possible additive cardiotoxicity between protein kinase inhibitors and hydroxychloroquine, azithromycin or lopinavir
- Many anticancer drugs can inhibit or induce CYPs which can change the bioavailability or elimination of lopinavir/r, hydroxychloroquine, favipiravir, or remdesivir

Anti-Cancer drugs: cytotoxic, targeted therapy

- When co-administered with hydroxychloroquine, calcineurin inhibitors and m-TOR inhibitors can cause QT prolongation
- Increased exposure of hydroxychloroquine with ciclosporin
- Must reduce dose of lopinavir/r with immunosuppressants due to its strong inhibition of CYP3A, OATP1B1, and OATP1B3 to prevent nephrotoxicity and neurotoxicity  
- Therapeutic drug monitoring needed in combination with lopinavir/r
- Baricitinib may increase immunosuppression in combination with immunosuppressants 
- Combination of anakinra and methotrexate or TNF-alpha not recommended 

Drugs in organ transplantation and autoimmune disease

Antidepressants:
- Do not combine citalopram or escitalopram with hydroxychloroquine due to risk of torsades de pointes by increasing the QT interval

Anxiolytics:
- Use of hydroxyzine with hydroxychloroquine is contraindicated due to the torsadogenic risk

Antipsychotics:
- Increased torsadogenic potential of most neuroleptics with hydroxychloroquine but combination not contraindicated

Addiction medication:
- Methadone not recommended with hydroxychloroquine due to dose dependent cardiotoxicity like torsades de pointes

Anti migraines:
- Use of azithromycin is contraindicated with ergot derivatives, ergotamine and dihydroergotamine

Antiepileptics: 
- Risk of interactions from old anticonvulsants including but not limited to phenytoin and phenobarbital due to enzyme inducing effects

Drugs in neuropsychiatric diseases

Anti-asthmatics:
- Ritonavir was show to increase the plasma exposure of fluticasone by more than 100 times and thus this combination should be avoided
- Strong CYP3A4 inhibitors like lopinavir/r can increase exposure of budesonide and salmeterol
- Increased salmeterol exposure can lead to QT prolongation and palpitations
- Theophylline exposure may be altered by lopinavir/r so both must be used with caution

Drugs in respiratory diseases

- Paracetamol
- NSAIDs
- Opioid Analgesics 

Antipyretics and Analgesics

- Anticoagulants and antiplatelet drugs
- Lipid lowering drugs
- Anti-hypertensives
- Drugs in heart failure
- Drugs in angina pectoris
- Anti-arrhythmic drugs
- Oral anti-diabetics

Drugs in Cardiovascular Disease

- Antiretrovirals
- Viral Hepatitis B and C Drugs
- Anti-tuberculosis Drugs

Drugs in Infectious Disease

- 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

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

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

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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