Major Neurologic Adverse Drug Reactions, Potential Drug–Drug Interactions and Pharmacokinetic Aspects of Drugs Used in COVID-19 Patients with Stroke: A Narrative Review

Figures & data

Table 1 A Brief Pharmacokinetic Data of Potential Drugs Used in COVID-19 Management²⁰

Anti-COVID-19 Agent	Bioavailability (F)	Volume of Distribution (Vd)	Elimination half-life (T ½)	Clearance (Cl)	Distribution	Metabolism	Route of Elimination
Chloroquine (CQ)	67–114%	200–800 L/kg	20 to 60 days	0.35–1 L/h/kg	Wide distribution to many body tissues containing the heart, kidneys, liver, eyes, leukocytes, and lungs. It could obtain prolonged deposition in the lungs.	Partially hepatic to the main metabolite, desethylchloroquine. Metabolized by CYP2C8^a, CYP3A4, and to a lesser extent CYP2D6.	Predominantly eliminated in the urine.
Hydroxy chloroquine (HCQ)	67–74%	63 L/kg	20 to 120 days	5.76 L/h	In comparison with chloroquine, it has a more limited distribution to body tissues.	Hepatic; metabolites include bidesethylchloroquine, desethylhydroxychloroquin, and desethylchloroquine Metabolized by CYP2C8, CYP3A4, and to a lesser extent CYP2D6	40–50% is excreted renally
Lopinavir	25%	1–1.5 L/kg	6.9 ± 2.2 hours	6–7 L/h	It could be distributed to body tissues except the brain.^Citation21	Hepatic via CYP3A4; 13 metabolites identIfied; may induce its own metabolism	Primarily eliminated in the feces (82.6 ± 2.5%) and the remaining excreted in the urine.
Ritonavir	Variable; increased with food.	0.41 ± 0.25 L/kg	3 to 5 hours	8.8 ± 3.2 L/h	It could obtain a high concentration in plasma and lymph nodes but limited distribution to body tissues.	Hepatic via CYP3A4 and 2D6; five metabolites, low concentration of an active metabolite (M-2) achieved in plasma (oxidative)	Primarily eliminated in the feces (86.4 ± 2.9%) and the remaining excreted in the urine.
Atazanavir	60–68%; enhanced with food.	1.4 L/kg	7 hours (increased to 12 hours in hepatically impaired patients)	9.4 L/h	It has a highly variable distribution into body fluids.^Citation22	Hepatic metabolism via CYP3A, also undergoes biliary elimination.	Primarily eliminated in the feces (79%)
Interferon-alpha	IM: 83% SubQ: 90%	1.4 L/kg	2 to 3 hours	0.231 L/h/kg	It has wide distribution to body tissues especially in patients with leukemia (up to 20-folds). Interferon alpha could not penetrate CSF^b.	Primarily renal, filtered and absorbed at the renal tubule	Renal clearance
Umifenovir	Rapid absorption	Not available	17 to 21 hours	99 ± 34 L/h	It has rapid absorption and distribution to different organs and tissues.^Citation23	Mainly metabolized by the liver, it should be used with caution in patients with liver dysfunction.	The major route of elimination is via the feces
Favipiravir	97.6%	11–13.7 L/kg	2 to 5.5 hours	2.98±0.30 L/h	It may present rapid uptake and clearance from the liver, kidneys, and intestine during first dose administration. But in multiple-dose administration, plasma concentration may be diminished while drug distribution and accumulation in the liver, stomach, and brain would be enhanced significantly.^Citation24	A genetic variant in digestive transport [Pgpk^c; ABCB1^d] and metabolism [aldehyde oxydase] to an inactive M1, urinary excretion; both metabolized by and inhibited by aldehyde oxidase	Predominantly renal clearance
Remdesivir	Not available	Not available	0.39 hour	Not available	It has rapid distribution in PBMCs^e and conversion to its active form.^Citation25	Predominantly metabolized to a triphosphate metabolite.	Not available
Tocilizumab	SubQ: 80%	0.054 L/kg	Concentration-dependent; up to 16 days	Concentration-dependent; Mean: 0.29 ± 0.10 mL/h/kg	It might distribute to lymphatic, hematopoietic, digestive, endocrine, muscular, neural, respiratory, urinary systems, etc.^Citation26 Vd in adults is up to 2-folds in children.	Not available	Biphasic elimination from the circulation
Ivermectin	Well absorbed; Improved absorption with high fat meal.	3 to 3.5 L/kg	16 to 18 hours	1.2 L/h	It may obtain high drug concentration in liver and adipose tissues, but has poor penetration through blood brain barrier.	Primarily hepatic metabolism.	Metabolized in the liver; ivermectin and/or its metabolites are excreted almost exclusively in the feces, Urine (<1%)
Teicoplanin	Oral: poorly absorbed IM: 90%	0.86 L/kg	70 to 100 hours	0.0033 L/h/kg	Tissue distribution of teicoplanin is highly variable. It may present extensive distribution to liver tissue but poor penetration into CSF.^Citation27	Metabolic transformation due to hydroxylation in the omega-2 and omega-1 positions for metabolites 1 and 2, respectively, of the C-10 linear side chain of component A2-3.	Not available
Azithromycin	37%	31.1 L/kg	68 hours	37.8 L/h	Extensively distributed to body tissues including skin, tonsil, lungs, sputum, etc. but has poor distribution to brain tissues due to limited CSF penetration.	Hepatic metabolism to inactive metabolites	Biliary excretion (major route) Urine (<6%)

Notes: ^aCytochrome P450 (CYP) 2C8. ^b Cerebrospinal fluid. ^cP-glycoprotein. ^dATP-binding cassette sub-family B member 1. ^ePeripheral blood mononuclear cells.

Table 2 The Common Central Nervous System (CNS) and Peripheral Nervous System (PNS) Adverse Effects of Drugs Used in COVID-19 Management

Drug	CNS Adverse Reactions	PNS Adverse Reactions
Chloroquine (CQ)	Acute confusional state,^Citation28 delirium,^Citation29 decreased deep tendon reflex, depression, extrapyramidal disorders,^Citation30 seizure^Citation31	Myopathy,^Citation32 neuromuscular disease, polyneuropathy
Hydroxychloroquine (HCQ)	Ataxia, vertigo, dizziness, sensorineural hearing loss, neurosis, psychosis, seizure	Myopathy^Citation33
Umifenovir	Dizziness, psychiatric symptoms (0.83%)^Citation34
Lopinavir/Ritonavir	Fatigue, headache, anxiety (4%), insomnia	Weakness, myalgia
Interferon alpha	Fatigue, headache, depression, drowsiness (1 to 33%), dizziness, vertigo, malaise, paresthesia, confusion (≤12), insomnia	Myalgia, asthenia, musculoskeletal pain, arthralgia, back pain
Favipiravir	Psychiatric reactions (1.72%)^Citation34
Remdesivir	Have not reported yet.	Have not reported yet.
Tocilizumab	Headache, dizziness (rare)	Chronic inflammatory demyelinating polyneuropathy (<1%)
Corticosteroids	Psychosis (14%),^Citation35,Citation36 mania (28%), depression (41%), delirium,^Citation36 anxiety,^Citation36 insomnia,^Citation36 seizure, vertigo, paresthesia,^Citation37 pseudotumor cerebri^Citation38,Citation39	Myopathy,^Citation40 neuropathy^Citation41,Citation42

Table 3 Potential Drug–Drug Interactions in COVID-19 Patients with Predisposing Cerebrovascular Diseases

Table 4 Possible Mechanisms, Types of Interactions, and Management of X-Category Drug–Drug Interactions

	Types of Interaction	Mechanism of Interaction	Interaction Management
Lopinavir/Ritonavir or Atazanavir plus Clopidogrel	Pharmacokinetic	Ritonavir and atazanavir might inhibit clopidogrel (a pro-drug) metabolism to its active metabolite so it result in the diminished antiplatelet activity.	Avoid combinations and consider possible alternatives.
Lopinavir/Ritonavir or Atazanavir plus Ticagrelor	Pharmacokinetic	Strong CYP3A4^a inhibitors would enhance the serum concentration of ticagrelor and reduce the serum concentration of its active metabolites.	Avoid a combination of ticagrelor with strong CYP3A4 inhibitors and consider alternatives.
Lopinavir/Ritonavir or Atazanavir plus Rivaroxaban	Pharmacokinetic	Since rivaroxaban is a substrate for both CYP3A4 isoenzyme and P-gp^b, concomitant administration of this drug with strong inhibitors of CYP3A4 and inhibitors of P-gp may enhance the serum concentration of rivaroxaban and risk of major bleeding.	Avoid a combination of rivaroxaban with strong CYP3A4 inhibitors and P-gp inhibitors.
Lopinavir/Ritonavir or Atazanavir plus Apixaban	Pharmacokinetic	These concomitant administrations might result in inhibition of CYP3A4 mediated metabolism and P-gp induced efflux of apixaban which may cause enhanced serum concentration of apixaban and bleeding complications.	A combination of apixaban with strong CYP3A4 inhibitors and P-gp inhibitors is contraindicated.
Lopinavir/Ritonavir or Atazanavir plus Edoxaban	Pharmacokinetic	Inhibitors of P-gp/ABCB1^c might enhance the Cmax^d, AUC^e, and anticoagulant effect of edoxaban.	A combination of edoxaban with P-gp/ABCB1 inhibitors should be avoided or dose adjustment should be considered in patients with venous thromboembolism. No dosage modification is available in patients with non-valvular atrial fibrillation.
Lopinavir/Ritonavir or Atazanavir plus Dabigatran etexilate	Pharmacokinetic	Inhibitors of P-gp/ABCB1 could enhance the serum concentration of active metabolites of dabigatran etexilate, which is a pro-drug agent. These drug–drug interactions would be significantly precipitated in patients with moderate to severe renal failure.	Avoid combination or consider therapy modification. Dose adjustment may also be considered according to the patients’ renal function, dabigatran etexilate indications, and labeling recommendations.

Notes: ^aCytochrome P450 (CYP) 3A4. ^bP-glycoprotein. ^cATP-binding cassette sub-family B member 1. ^dMax serum concentration. ^eArea under the curve.

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