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

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

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)

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:

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

• Inducer of: CYP2C9, CYP2C19, 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

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 metabolised 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: Nicotinamide adenine dinucleotide phosphate (NADPH) independent and dependent enzymes.
• Inhibits:
  • CYP2C8 (strong)
  • OAT1, OAT3 (mod)
  • CYP1A2 (weak) , CYP2C9 (weak) , CYP2C19 (weak) , CYP2CD6 (weak) , CYP2E1 (weak) , CYP3A4 (weak)

• 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:

• May be dispersible or crushed– check 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 effected by these CYP enzymes is unknown.