Neurologic Disorders and COVID-19

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ;Fahimeh Shojaei, M.D.;Niloofarsadaat Eshaghhosseiny, MD[2];Rinky Agnes Botleroo, M.B.B.S.

Complications in the Central Nervous System

Cerebrovascular Accident/Stroke

• Hemorrhagic
• Ischaemic

Complications due to medication interaction

1. Statin induced myotoxicity

• Myalgia, myopathies, rhabdomyolysis

2. 2nd and 3rd degree atrioventricular block

• Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)

3. Prolong QTc interval

• Chloroquine/Hydroxychloroquine
• Azithromycin

4. Myelotoxicity

• Ribavirin

5. Prolonged PR interval

• Atazanavir

COVID-19 Experimental Treatments with Interaction Potential

1. Remdesivir (GS‐5734)

Pharmacokinetics and Dosing:

• Adults ≥40 kg: Daily IV dose over 30 min.

Day 1: 200 mg, Day 2‐10: 100 mg

• Paed <40 kg: Daily IV dose over 30 min. Day 1: 5 mg/kg, Day 2‐10: 2.5 mg/kg

ClinicalTrials.gov Identifier:

• NCT04302766
• NCT04292899

Interaction Potential:

• Inhibits: CYP3A4, OATP1B1/3, BSEP, MRP4, and NTCP
• Induces: CYP1A2 and CYP2B6
• Unlikely clinically significant (all in vitro data)
• Concurrent use with hydroxychloroquine- decreases the antiviral activity of remdesivir.

2. Lopinavir/ Ritonavir (Kaltera) (400 mg/100 mg)

Pharmacokinetics and Dosing:

• 400mg/100mg twice daily for 14 days
• Crushing tablet ↓ absorption ≅ 45%133.
• Use oral liquid (42.4% alcohol and 15.3% propylene glycol)
• Use compatible feeding tubes (PVC or silicone)
• Avoid metronidazole and disulfiram
• Absorbed in jejunum: NG ok; NJ may ↓ effect

ClinicalTrials.gov Identifier:

• NCT04276688

Chinese Clinical Trials Registry ID:

• ChiCTR2000029539

EU Clinical Trials Register ID:

• 2020‐000936‐23

Interaction Potential:

• Lopinavir extensively metabolized by CYP3A
• Inhibitor of CYP3A4 (potent), P‐gp, BCPR, and OATP1B1
  • can increase concentration of drugs metabolized or substrates of these pathways

• Inducer of CYP2C9, CYP2C19, and glucuronidation

• Can prolong PR interval.
• Rare reports of 2nd and 3rd-degree atrioventricular block in patients with underlying risk factors

3. Chloroquine/Hydroxychloroquine

Pharmacokinetics and Dosing:

• 200 mg three times a day for 10 days

ClinicalTrials.gov Identifier:

• NCT04261517

Chinese Clinical Trials Registry ID:

• ChiCTR2000029609

Interaction Potential:

• Metabolised by CYP2C8, CYP3A4, CYP2D6
• Inhibited by CYP2D6 and P‐gp
• Can prolong QTc interval, consider ECG monitoring where appropriate
• Concurrent use of HCQS with antibiotic azithromycin causes chest pain, congestive heart failure.
• Antacids decrease the absorption of hydroxychloroquine.
• Neostigmine, pyridostigmine antagonize the action of hydroxychloroquine.

4. Interferon beta

ClinicalTrials.gov Identifier:

• NCT04276688

Interaction Potential:

• Interferons have been reported to reduce CYP450 drug metabolism
• Care with narrow therapeutic index drugs dependent on CYP450 clearance

5. Ribavirin

Pharmacokinetics and Dosing:

• Do not crush – known teratogen.
• Contact hospital pharmacy for solution compounded from capsules or (SAS) product availability

ClinicalTrials.gov Identifier:

• NCT04276688

Interaction Potential:

• Not metabolized by CYP450 unlikely to contribute to CYP interactions.
• Inhibits inosine monophosphate dehydrogenase:
• Can interfere with azathioprine metabolism possibly leading to accumulation of 6‐methylthioinosine monophosphate (6‐MTIMP), which has been associated with myelotoxicity

6. Favipiravir

Chinese Clinical Trials Registry ID:

• ChiCTR2000029600 (favipiravir plus interferon‐α)
• ChiCTR2000029544 (favipiravir plus baloxavir marboxil)

Interaction Potential:

• Metabolised by aldehyde oxidase in the cytosol of the liver.
• Inhibits:
  • CYP2C8 (strong)
  • OAT1, OAT3 (mod)
  • CYP1A2 (weak) , CYP2C9 (weak) , CYP2C19 (weak) , CYP2CD6 (weak) , CYP2E1 (weak) , CYP3A4 (weak)
  • Aldehyde oxidase Inhibitors increase the concentration of favipiravir. The drugs include selective estrogen receptor modulators(SERMs), H2 receptor antagonists like cimetidine, calcium channel blockers, anti-arrythmic drugs like propafenone, tricyclic antidepressants.

• Low-risk QT prolongation

7. Atazanavir

Pharmacokinetics and Dosing:

• Requires pH <4.
• Avoid antacids 2 h before and 1 hour after.
• Food ↑ bioavailability
• Absorbed in jejunum: NG ok; NJ may ↓ effect

Interaction Potential:

• Metabolised by: CYP3A4 (extensively)
• Inhibits: CYP3A4, UGT1A1, OATP1B1 (strong), CYP2C8 (weak)
• Absorption depends on low pH; drugs increasing pH will decrease atazanavir concentration
• Dose-related prolongation in PR interval.
• Care with drugs increasing QT interval or in patients with pre‐existing risk factors.

8. Nitazoxanide (prodrug) (active metabolite: tizoxanide)

Pharmacokinetics and Dosing:

• Maybe dispersible or crushed– check the brand
• Take with food ‐ increases bioavailability by 50%.

Interaction Potential:

• Nil effects on CYP450 enzymes
• Tizoxanide highly protein-bound (>99.9%)
• Will compete for binding sites; monitor drugs highly protein-bound with a narrow therapeutic index (such as warfarin)

9. Tocilizumab (IL‐6 monoclonal antibody)

Pharmacokinetics and Dosing:

ClinicalTrials.gov Identifier:

• NCT04310228
• NCT04306705

Interaction Potential:

• Nil significant drug interactions.
• COVID‐19 increases IL‐6 expression. Tocilizumab reduces IL‐6 expression. IL‐6 increases CYP3A4, CYP26C19, CYP2C9, CYP1A2. When tocilizumab is used to treat COVID‐19, the effect on drugs affected by these CYP enzymes is unknown.

10. Dexamthasone

Pharmacokinetics and Dosing:

• Oral or Intravenous- 6mg/day for 10 days
• Given in patients who are mechanically ventilated.

Clinical Trial:

• Randomised Evaluation of COVID-19 Therapy (RECOVERY) Trial

Interaction Potential:

• Interacts with many drugs like oral contraceptive pills, digoxin, blood thinners ( clopidogrel, warfarin, dabigatran )

11. Ivermectin:

• It is not FDA approved for use in SARS-CoV2

Pharmacokinetics:

• Metabolised by liver microsomes by Cyt P450-3A4

Research Trial:

• A study by a National Breast Cancer Foundation Fellowship, Australia (ECF-17-007) for KMW and an National Health and Medical Research Council (NHMRC), Australia Senior Prinicple Research Fellow (SPRF) (APP1103050) for DAJ, found Ivermectin to be effective in treating SARs-CoV2.
  

Interactions:

• Ivermectin increases the side effects of blood thinners.

• Grapefruit juice increases the concentration of ivermectin.
• Avoid or limit alcohol use in patients taking ivermectin.