Ritonavir-boosted nirmatrelvir

Nirmatrelvir-ritonavir (Paxlovid)

• Combination of oral protease inhibitors
• Preferred option for СΟVΙD-19-specific therapy for symptomatic outpatients with risk for progression to severe disease
• Substantially reduces the risk of hospitalization and mortality in some high-risk outpatients who have mild to moderate СOVID-19 (i.e., no hypoxia).

Indications

• Confirmed COVID-19 (at home or in-clinic test).
• Patients who are at highest risk for progressing to severe disease.
• Initiated within 5 days of symptom onset.

Particularly recommended for those who:

• Are 65 years or older, or
• Are immunocompromised, or
• Have multiple medical comorbidities.

Dosing

Adult Dosing

• eGFR ≥ 60 mL/min: 300 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
• eGFR ≥ 60 mL/min: 150 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
• eGFR < 30 mL/min: Not recommended.

Pediatric Dosing

Children ≥ 12 years old, weighing ≥40 kg:

• eGFR ≥ 60 mL/min: 300 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
• eGFR ≥ 60 mL/min: 150 mg nirmatrelvir plus 100 mg ritonavir orally, twice daily, for 5 days.
• eGFR < 30 mL/min: Not recommended.

Drug Interactions

Nirmatrelvir-ritonavir:

• An inhibitor of metabolic enzymes and transporters such as the CYP3A enzyme (predominantly because of the ritonavir component), and
• A substrate of CYP3A [1].

Prior to prescribing, review the patient's medications' list and assess specific drug interactions and potential ways to mitigate them. For example:

• Drug interactions program included with UpToDate
• Drug interaction checker from the University of Liverpool

Adverse Reactions

• 1% to 10%: Gastrointestinal: Diarrhea (3%), dysgeusia (5%)

Postmarketing:

• Cardiovascular: Bradycardia, hypertension, syncope
• Dermatologic: Pruritus, severe dermatological reaction (including Stevens-Johnson syndrome and toxic epidermal necrolysis), skin rash
• Gastrointestinal: Abdominal pain, nausea, pancreatitis, vomiting
• Hypersensitivity: Anaphylaxis, hypersensitivity reaction
• Nervous system: Headache, malaise
• Respiratory: Dyspnea

Special Populations

Pregnancy Rating

• US FDA pregnancy category: Not assigned.
• Nirmatrelvir-ritonavir should not be used during pregnancy unless the benefit outweighs the risk to the fetus.

Lactation risk

• Information related to COVID-19 and breastfeeding is available from the World Health Organization

Renal Dosing

Addressed above in "Dosing" section.

Hepatic Dosing

• Adult:
  • Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
  • Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

• Pediatric (≥12 years old, weighing ≥40 kg):
  • Mild or moderate impairment: No dosage adjustment necessary.
  • Severe impairment: Not recommended for use (has not been studied).

Contraindications

• Allergy to class/drug
  • Many drug interactions
  • E.g. Plavix, Phenytoin, Tacrolimus, Tramadol, Statins, Hydro/oxycodone/Codeine, Diazepam/Clonazepam/Alprazolam, Fentanyl, Tamsulosin

Pharmacology

• Metabolism: Νirmatrelvir (when given with ritonavir): Minimal; Ritonavir: Hepatic via CYP3A4 (major) and CYP2D6 (minor).
• Time to peak: Νirmаtrelvir (when given with ritonavir): 3 hours; Ritonavir: 3.98 hours.
• Half-life: Νirmаtrelvir (when given with ritonavir): 6.05 hours; Ritonavir: 6.15 hours.
• Excretion: Nirmаtrelvir (when given with ritonavir): Feces (27.5%); urine (55%); Ritonavir: Feces (86.4%); urine (3.5%).

Mechanism of Action

• Nirmаtrelvir blocks the activity of the ЅΑRS-CoV-2-3CL protease, an enzyme required for viral replication.
• Co-administration of nirmаtrelvir with ritonavir slows the metabolism of ոirmatrelvir so it remains active in the body for longer and at higher concentrations.

Comments

• 89% reduction in hospitalization or death in high risk population, and 70% reduction in hospitalizations with no deaths in standard risk population.

References

1. Prescribing Nirmatrelvir-Ritonavir: How to Recognize and Manage Drug-Drug Interactions (https://pubmed.ncbi.nlm.nih.gov/35226530/)
2. UpToDate: Nirmatrelvir and ritonavir: Drug information (https://www.uptodate.com/contents/nirmatrelvir-and-ritonavir-drug-information)
3. UpToDate: COVID-19: Management of adults with acute illness in the outpatient setting (https://www.uptodate.com/contents/covid-19-management-of-adults-with-acute-illness-in-the-outpatient-setting)