What is the primary metabolism pathway of Paxlovid (nirmatrelvir and ritonavir)?

Paxlovid Metabolism Pathways

Primary Metabolism

Nirmatrelvir is primarily metabolized by CYP3A4, but when co-administered with ritonavir in Paxlovid, metabolic clearance becomes minimal and renal elimination becomes the dominant pathway. 1

Nirmatrelvir Metabolism and Elimination

• Nirmatrelvir is a CYP3A substrate, but ritonavir's potent CYP3A4 inhibition drastically reduces its hepatic metabolism 1, 2
• Renal elimination becomes the primary route when nirmatrelvir is dosed with ritonavir, with 55.0% of the dose excreted unchanged in urine 1
• Fecal elimination accounts for 27.5% of the dose as unchanged drug 1
• The oral clearance (CL/F) is 8.99 L/hr with a half-life of approximately 6.05 hours 1

Ritonavir's Role as Pharmacokinetic Enhancer

• Ritonavir functions as a CYP3A inhibitor (not as an antiviral against SARS-CoV-2), specifically included to boost nirmatrelvir plasma concentrations 1, 2
• Ritonavir itself is metabolized primarily by CYP3A (major pathway) with minor metabolism through CYP2D6 1
• Ritonavir undergoes predominantly hepatic metabolism with 86.4% of drug-related material excreted in feces and only 3.5% as unchanged drug in urine 1
• The oral clearance of ritonavir is 13.92 L/hr with a half-life of 6.15 hours 1

Clinical Implications of Metabolism Pathways

Drug Interaction Mechanism

• Ritonavir causes potent and rapid inhibition of CYP3A4, creating significant drug-drug interaction potential even with the short 5-day treatment course 3
• Approximately 60% of available medications undergo at least partial oxidative metabolism via CYP3A4, making ritonavir a significant source of drug interactions 4
• Ritonavir also inhibits CYP2D6 and P-glycoprotein (P-gp) transporter protein to a lesser extent 2, 3
• Nirmatrelvir functions as both a substrate and inhibitor of CYP3A enzymes and P-gp transporter protein 5

Contraindicated Medications Due to CYP3A4 Inhibition

The following drugs are absolutely contraindicated with Paxlovid due to ritonavir's strong CYP3A4 inhibition: 6

• Statins: lovastatin, simvastatin, atorvastatin (increased risk of rhabdomyolysis) 6
• Sedatives/hypnotics: oral midazolam, triazolam (increased risk of prolonged sedation) 6
• Antipsychotics: quetiapine (increased risk of toxicity) 6
• Cardiovascular drugs: alfuzosin, amiodarone, quinidine, salmeterol 7
• Pulmonary hypertension drugs: sildenafil when used for pulmonary arterial hypertension 6
• Ergot derivatives, cisapride, astemizole, terfenadine 7

Enzyme Inducers That Compromise Efficacy

• Strong CYP3A4 inducers are contraindicated as they reduce nirmatrelvir exposure and compromise antiviral efficacy 7
• These include: carbamazepine, phenytoin, phenobarbital, rifampicin, St. John's wort, enzalutamide 7

Renal Impairment Considerations

• In moderate renal impairment (eGFR 30-60 mL/min), nirmatrelvir AUC increases by 87%, requiring dose reduction to 150 mg/100 mg twice daily 1
• In severe renal impairment (eGFR <30 mL/min), nirmatrelvir AUC increases by 204% with standard dosing 1
• For severe renal impairment requiring or not requiring hemodialysis, the recommended regimen is 300 mg/100 mg once on Day 1, followed by 150 mg/100 mg once daily on Days 2-5 1
• During hemodialysis, approximately 6.9% of nirmatrelvir is cleared through dialysis 1

Hepatic Impairment Considerations

• No dose adjustment is needed for mild-to-moderate hepatic impairment (Child-Pugh Class A or B), as nirmatrelvir pharmacokinetics remain similar 1
• The impact of severe hepatic impairment (Child-Pugh Class C) has not been studied 1

Common Pitfalls to Avoid

• Do not assume brief 5-day treatment minimizes interaction risk - ritonavir causes rapid and potent CYP3A4 inhibition that can lead to serious toxicities even with short-term use 3
• Always check immunosuppressant levels - tacrolimus should be discontinued or given as a microdose on day 1, while cyclosporine should be reduced to 20% of initial dose 8
• Monitor anticoagulants closely - warfarin and rivaroxaban toxicity risk is enhanced by concomitant Paxlovid administration 5
• Consult drug interaction databases such as the Liverpool COVID-19 Drug Interaction tool for comprehensive medication review before prescribing 6