Generic Name

Paxlovid

Mechanism

• Nirmatrelvir selectively binds to the active site of the SARS‑CoV‑2 main protease (Mpro / 3CLpro), blocking proteolytic cleavage of the viral polyprotein.
• Inhibition of Mpro prevents synthesis of *nonstructural proteins* required for viral replication.
• Ritonavir is not antiviral by itself; it inhibits CYP3A4 and P‑gp, thereby sustaining serum concentrations of nirmatrelvir and prolonging its antiviral effect.
• The combination results in a rapid, sustained suppression of viral load when started within 5 days of symptom onset.

Pharmacokinetics

• Absorption – Oral bioavailability of nirmatrelvir is ~55 % with a median Tmax of 1 h; ritonavir slightly prolongs absorption.
• Distribution – Highly protein‑bound (≈94 %).
• Metabolism – Primarily metabolised by CYP3A4 (decreased by ritonavir).
• Elimination – Renal excretion dominates: ~55 % of nirmatrelvir is recovered unchanged in urine; ritonavir is eliminated hepatically.
• Half‑life – Nirmatrelvir: ~3.2 h (unchanged), ritonavir: ~5–6 h; steady‑state achieved by Day 2.
• Clinical Implications – Drug‑drug interactions are common, especially with CYP3A4 substrates (statins, anti‑arrhythmics, anticoagulants). Screen medication lists before initiation.

Indications

• Outpatient treatment of mild to moderate COVID‑19 in patients at high risk for disease progression (age ≥60, BMI ≥35, chronic kidney disease, immunosuppression, etc.).
• Efficacy demonstrated for all circulating strains, including Omicron subvariants, in the EPIC‑HR trial.
• Not indicated for hospitalized patients with severe or critical disease; these patients may receive remdesivir or monoclonal antibodies.

Contraindications

• Contraindicated in patients with moderate‑to‑severe hepatic impairment (Child‑Pugh B or C).
• Caution with severe renal dysfunction (CrCl < 30 mL/min); dose adjustment required.
• QTc interval prolongation: avoid concomitant drugs that also prolong QT (eg, azithromycin, hydroxychloroquine).
• Known hypersensitivity to nirmatrelvir, ritonavir, or excipients.
• Pregnancy: data limited; use only if benefits outweigh risks.
• Breastfeeding: not recommended without adequate evidence.

Dosing

• Regimen: 5 consecutive days, 300 mg nirmatrelvir + 100 mg ritonavir taken twice daily (≈12 h apart).
• Administration: Oral tablets with or without food; high‑fat meals may modestly increase exposure.
• Timing: Initiate within 5 days of symptom onset; earlier administration yields greater benefit.

Adverse Effects

Common (≤10 % incidence)
• Dysgeusia
• Diarrhea
• Nausea
• Headache
• Fatigue

Serious (>1 % or rare)
• Hypersensitivity reactions (rash, angioedema)
• QTc prolongation → ventricular arrhythmias
• Hepatotoxicity (ALT/AST elevation)
• Renal dysfunction (rare)

Monitor liver enzymes and renal markers if clinically indicated.

Monitoring

• Baseline labs: CBC, CMP (including ALT, AST, bilirubin), electrolytes, CrCl.
• Drug interactions: Review all patient medications; discontinue or dose‑adjust interacting drugs.
• QTc: Baseline ECG if on QT‑prolonging agents; repeat if clinically warranted.
• Adverse event surveillance: Report new rash, angioedema, or significant GI symptoms.

Clinical Pearls

• Early is critical: A 5‑day course started within 3 days of symptom appearance reduces hospitalization risk by ~87 %.
• No dosage adjustment for body weight beyond renal considerations; the same fixed dose applies to ≥40 kg patients.
• Ritonavir’s role is pharmacokinetic, not antiviral; this facilitates high nirmatrelvir trough levels.
• Drug‑interaction vigilance: Medications like statins (especially lovastatin, simvastatin), dabigatran, and certain antiepileptics necessitate careful review.
• Pediatric use: Approved for ≥12 years, ≥40 kg; dose‑reductions mirror adult adjustments for renal function.
• Pregnancy consideration 3: In the absence of robust data, evaluate therapy risk–benefit on a case‑by‑case basis.
• Vaccinated vs. unvaccinated: Both groups benefit; however, vaccination plus Paxlovid confers the lowest risk for progression.
• Mechanism‑driven resistance: Mpro mutations may reduce efficacy; continue surveillance for emerging variants.
• Patient education: Emphasise adherence to the full 5‑day course; missing doses can increase the risk of rebound viral replication.

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• Paxlovid offers a potent, short‑course oral option for high‑risk COVID‑19 patients, leveraging a targeted protease inhibition strategy and pharmacokinetic boosting. Use with careful attention to renal function, hepatic status, and drug‑drug interactions to maximise therapeutic benefit.