Nirmatrelvir-Ritonavir

Mechanism of Action

Nirmatrelvir/ritonavir is a combination of two medications with distinct mechanisms of action. Nirmatrelvir, the first component, is a peptidomimetic inhibitor of Mpro, the SARS-CoV-2 main protease. Inhibiting Mpro prevents the virus from processing the polyprotein precursors it requires for viral replication.

Ritonavir, the second component, is a human immunodeficiency virus-1 (HIV-1) protease inhibitor with CYP3A-inhibiting effects. The latter effect allows it to be used as a pharmacokinetic boosting agent to decrease the CYP3A-mediated metabolism of nirmatrelvir. Coadministration of nirmatrelvir with ritonavir is needed to increase the plasma concentration of nirmatrelvir enough to achieve the targeted therapeutic range.[15] 

Nirmatrelvir/ritonavir is effective against major variants of SARS-CoV-2, including omicron variants.[16] The proposed mechanism of resistance is the possibility of potential escape mutations.[17]

Pharmacokinetics

Absorption: The time to maximum plasma concentration (Tmax) for nirmatrelvir(coadministered with ritonavir) is approximately 3 hours. Administering high-fat meals with nirmatrelvir/ritonavir increases the rate and extent of absorption.

Distribution: Plasma protein binding (PPB) for nirmatrelvir is 69% (coadministered with ritonavir), PPB of ritonavir 98-99%. The mean volume of Distribution for nirmatrelvir is 104.7 L (coadministered with ritonavir).

Metabolism: Nirmatrelvir is a human cytochrome CYP3A4 substrate, but when administered with ritonavir, the metabolic clearance is minimal. Ritonavir inhibits the metabolism of nirmatrelvir, leading to increased plasma concentrations of nirmatrelvir. Ritonavir is also metabolized by CYP2D6(minor).

Excretion: The primary route of elimination for nirmatrelvir is renal, whereas ritonavir is eliminated primarily by hepatic metabolism in feces.[18]

Administration

The standard regimen is nirmatrelvir 300 mg (two 150 mg tablets) and ritonavir 100 mg (one 100 mg tablet), which are orally co-administered twice daily for five days and started within five days of symptom onset. Nirmatrelvir and ritonavir are co-packaged in convenience packs of 300 mg/100 mg or 150 mg/100 mg (for patients with moderate renal impairment).[3]

The medication should be taken at the same time each day. If a dose is missed within eight hours of the time it is typically assumed, it should be taken as soon as possible. However, the missed dose should be skipped if more than eight hours have elapsed. The FDA does not authorize nirmatrelvir/ritonavir for treatment for longer than five days. Additionally, use is not approved for pre-exposure or post-exposure prophylaxis to prevent COVID-19.

Use in Specific Patient Population

Renal Impairment

• Dose adjustment is not needed for mild renal impairment (eGFR >60 mL/min to <90 mL/min).
• Dose adjustment is needed for moderate renal impairment (eGFR >30 to <60 mL/min). 
• Nirmatrelvir 150 mg (one 150 mg tablet) and ritonavir 100 mg (one 100 mg tablet) are orally co-administered twice daily for five days within five days of symptom onset.
• Nirmatrelvir/ritonavir is not recommended in those with severe renal impairment (eGFR <30 mL/min).[19] Use the CKD-EPI formula to calculate eGFR.[20][21]

Hepatic Impairment

• Dose adjustment is not needed for mild hepatic impairment (Child-Pugh Class A).
• Dose adjustment is not needed for moderate hepatic impairment (Child-Pugh Class B).
• Nirmatrelvir/ritonavir is not recommended for those with severe hepatic impairment (Child-Pugh Class C).[3]

Pregnancy Considerations: Limited human data is available regarding drug-related risks of congenital disabilities, miscarriage, or other adverse maternal or fetal outcomes using nirmatrelvir in pregnant women. Human data on the use of ritonavir in pregnant women have not shown an increase in the risk of congenital disabilities.

Animal studies of nirmatrelvir/ritonavir suggest that it can be safely used in pregnant women. Because pregnancy is a risk factor for developing severe COVID-19, nirmatrelvir/ritonavir should be offered to eligible pregnant women based on risk-benefit assessments.[22]

Breastfeeding Considerations: Limited human data is available regarding the presence of nirmatrelvir in breast milk or its effects on breastfeeding infants. Human data demonstrate that ritonavir is present at low levels in breast milk and breastfed infants' blood.

Though ritonavir use during pregnancy is unlikely to have significant clinical implications, breastfeeding infants should still be monitored for the development of adverse effects. Additionally, nirmatrelvir has poor oral bioavailability, and the concentration of ritonavir in milk is small; consequently, the combination of nirmatrelvir/ritonavir is unlikely to cause adverse drug reactions in nursing infants.[23]

Adverse Effects

As nirmatrelvir/ritonavir is an investigational drug, there is limited clinical data about its potential adverse effects. However, data from the EPIC-HR trial suggests that it is generally well-tolerated by patients with COVID-19. The most common adverse effects include dysgeusia, diarrhea, hypertension, and myalgia.[3]

In addition, hypersensitivity reactions, which may manifest as urticaria, angioedema, pruritus, and dyspnea, have been reported. Cases of anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported with ritonavir use. Hyperlipidemia, hypertriglyceridemia,  and other metabolic adverse effects have also been noted with ritonavir.[24] 

Hepatic transaminase elevations have been reported, but transaminase elevations have also been attributed to COVID-19(A confounding factor). The risk of hepatotoxicity is low, and the Likelihood score is E:(unlikely cause of clinically apparent liver injury).[25]

Nirmatrelvir/ritonavir has significant drug-drug interactions due to the ritonavir component. As a potent CYP3A inhibitor, ritonavir can increase plasma concentrations of concomitant medications, increasing the risks of developing severe and life-threatening drug-related adverse effects. Due to these drug-drug interactions, many CYP3A-metabolized drugs are contraindicated in patients taking nirmatrelvir/ritonavir.[24]

In patients with undiagnosed or uncontrolled HIV-1 infection, there is a theoretical risk that the use of nirmatrelvir/ritonavir will facilitate the development of antiviral cross-resistance against HIV-1 protease inhibitors due to the ritonavir component, which is an HIV-1 protease inhibitor; hence nirmatrelvir/ritonavir use is cautioned in patients with undiagnosed or uncontrolled HIV-1 infection.[24]

Contraindications

Nirmatrelvir/ritonavir is contraindicated if the patient has a history of clinically significant hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis) to nirmatrelvir or ritonavir, other drugs in the same class, or drug components.[3]

Moreover, nirmatrelvir/ritonavir is contraindicated with the concomitant use of medications that depend on CYP3A for clearance and whose elevated plasma concentrations are associated with serious and life-threatening adverse reactions which are due to the CYP3A-inhibiting effects of ritonavir, which can increase plasma concentrations of those medications to dangerous levels.[26][27] 

Below is a partial list of those contraindicated medications and their potential adverse effects according to the FDA prescriber fact sheet.

• Alpha-1-adrenoreceptor antagonists (alfuzosin): hypotension
• Analgesics (pethidine): respiratory depression, hematologic abnormalities
• Antianginals (ranolazine): serious and life-threatening reactions
• Antiarrhythmics (amiodarone, dronedarone, flecainide, propafenone, quinidine): cardiac arrhythmias
• Anticancer drugs (encorafenib, ivosidenib): QT interval prolongation
• Anti-gout drugs (colchicine): severe and life-threatening reactions in renal or hepatic impairment
• Antipsychotics (lurasidone, pimozide, clozapine): cardiac arrhythmias
• Benign prostatic hyperplasia agents (silodosin): postural hypotension
• Cardiovascular agents (eplerenone): hyperkalemia
• Cardiovascular agents (ivabradine): bradycardia, conduction disturbances
• Ergot derivatives (dihydroergotamine, ergotamine, methylergonovine): acute ergot toxicity
• HMG-CoA reductase inhibitors (lovastatin, simvastatin): myopathy (including rhabdomyolysis)
• Immunosuppressants (voclosporin): acute and chronic nephrotoxicity
• Microsomal triglyceride transfer protein inhibitors (lomitapide): hepatotoxicity, gastrointestinal adverse effects(Possible increase of AUC 27 fold)
• Migraine medications (eletriptan, ubrogepant): cardiovascular and cerebrovascular adverse events
• Mineralocorticoid receptor antagonists (finerenone): hyperkalemia, hypotension, hyponatremia
• PDE5 inhibitors (sildenafil): visual abnormalities, hypotension, priapism, syncope
• Opioid antagonists (naloxegol): opioid withdrawal symptoms
• Sedatives/hypnotics (triazolam, oral midazolam): respiratory depression, extreme sedation
• Serotonin receptor 1A agonists/2A antagonists (flibanserin): hypotension, syncope, CNS depression
• Vasopressin receptor antagonists (tolvaptan): dehydration, hypovolemia, hyperkalemia

Furthermore, nirmatrelvir/ritonavir is contraindicated with the concomitant use of medications that are CYP3A inducers, which can decrease nirmatrelvir plasma concentrations to levels that result in loss of virologic response and development of antiviral resistance. This is due to nirmatrelvir/ritonavir being a CYP3A substrate whose plasma concentration is decreased by CYP3A inducers.

The following is a partial list of those contraindicated medications whose coadministration with nirmatrelvir/ritonavir can result in loss of virologic response and antiviral resistance. Below is a partial list of those contraindicated medications whose coadministration with nirmatrelvir/ritonavir can result in loss of virologic response and antiviral resistance.[26][27] 

• Anticancer drugs (apalutamide)
• Anticonvulsants (carbamazepine, phenobarbital, primidone, phenytoin)
• Antimycobacterial (rifampin)
• Cystic fibrosis drugs (lumacaftor/ivacaftor)
• Herbal products (St. John's Wort)

Management of Potential Drug-drug Interactions

• Ritonavir decreases the conversion to clopidogrel's active metabolite, leading to inadequate inhibition of platelet aggregation. Thus, it is recommended to avoid nirmatrelvir/ritonavir in patients at very high risk of thrombosis (e.g., early period post coronary stenting) unless clopidogrel can be switched to the noninteracting drug.[28][29]
• Ritonavir has been shown to increase rivaroxaban AUC significantly and can potentially increase the risk of bleeding; thus, concurrent administration with nirmatrelvir/ritonavir is not advised. The management of this drug interaction would require pausing rivaroxaban and switching to alternative agents for the anticoagulation (such as edoxaban or LMWH).[28][29]
• In patients receiving a ritonavir-boosted regimen with a calcineurin inhibitor(tacrolimus/cyclosporine), a significant increase in tacrolimus and cyclosporine exposure has been observed, which can lead to significant toxicity. Based on the clinical data, holding tacrolimus for eight days (i.e., five days during nirmatrelvir/ritonavir treatment and three days post-treatment) is recommended.[30]
• According to the French Society of Pharmacology and Therapeutics, coadministration of fentanyl with nirmatrelvir/ritonavir may increase the exposure of fentanyl with the risk of severe respiratory depression.[28][29]

Monitoring

Patients taking nirmatrelvir/ritonavir requires close monitoring for adverse reactions, such as hypersensitivity and drug-drug interactions.[7] Moreover, clinicians may consider therapeutic concentration monitoring of coadministered medications that CYP3A metabolizes. Certain medications, such as warfarin, may require additional monitoring of factors such as the international normalized ratio (INR).[31] Furthermore, clinicians may consider checking renal and liver function in patients taking nirmatrelvir/ritonavir, especially those with pre-existing renal and hepatic impairment.

TDM (Therapeutic drug monitoring) is required for narrow therapeutic drugs like cyclosporine and tacrolimus when coadministered with nirmatrelvir/ritonavir.[30][32]

Clinicians and healthcare facilities must be aware of mandatory reporting requirements. Prescribers are mandated to use FDA Form 3500 to report all medication errors and serious adverse events related to nirmatrelvir/ritonavir to FDA MedWatch(https://www.fda.gov/medwatch/report.htm). The adverse event must be reported to Pfizer according to the package insert. In addition, clinicians and healthcare facilities must report therapeutics information and utilization data to the US Department of Health and Human Services.

Clinicians should also monitor patients who complete their regimen of nirmatrelvir/ritonavir for rebound and recurrence of COVID-19 symptoms.[33] At this time, the mechanism, incidence, and implications of this rebound effect are unknown. According to the CDC and FDA, additional treatment with nirmatrelvir/ritonavir is not required when a rebound/recurrence is suspected.[34]

Toxicity

Nirmatrelvir/ritonavir has significant drug-drug interactions due to the ritonavir component. As a potent CYP3A inhibitor, ritonavir can increase the plasma concentrations of concomitant medications whose metabolism depends on CYP3A, increasing the risks of serious and life-threatening toxicities. In addition, ritonavir use is associated with hepatotoxicity, with reports of hepatitis, jaundice, and elevated transaminases. Patients taking nirmatrelvir/ritonavir, with or without other medications, should be monitored for drug-related toxicities.[24] 

In the event of an overdose of nirmatrelvir/ritonavir, management entails general supportive measures, including close monitoring of vital signs and observation of clinical status. There is no antidote specifically for an overdose of nirmatrelvir/ritonavir. The poison center should be contacted in the case of an overdose with nirmatrelvir/ritonavir for recommendations by medical toxicologists.[35]

Enhancing Healthcare Team Outcomes

As stated above, ritonavir is a potent CYP3A inhibitor with significant drug-drug interactions that can potentially cause life-threatening adverse events.[24] Therefore, the healthcare team must be extremely cautious when prescribing nirmatrelvir/ritonavir to patients taking other medications. An interprofessional team of clinicians, pharmacists, nurses, and other health professionals can minimize the risk of these drug-drug interactions and improve patient-centered care, health outcomes, and patient safety.

Clinicians and pharmacists (authorized under the FDA EUA to prescribe nirmatrelvir/ritonavir to eligible patients) should obtain a comprehensive history to determine whether patients are candidates for the medication.[36] Given the many known drug-drug interactions, the healthcare team should perform thorough medication reconciliation, including prescription and over-the-counter medications, herbal supplements, and recreational drugs.[37]

If potential drug-drug interactions exist, all healthcare team members should be informed to not only help prevent adverse events but also implement any corrective measures if necessary. In addition, dose adjustments of concomitant medications might be necessary for patients at risk of drug-drug interactions or those with moderate renal impairment.[19] Initial dosing and dose adjustments should be made under the guidance of a clinician and pharmacist.

Patients taking nirmatrelvir/ritonavir should be monitored by the interprofessional team. In addition, patients need to be provided with a fact sheet for patient education. Nurses are ideally situated to observe for adverse reactions, assess patient compliance with their regimen, and inform the healthcare team of their findings. However, as stated above, all healthcare team members are mandated to report serious medication errors and adverse events to FDA MedWatch and the drug's manufacturer.

As nirmatrelvir/ritonavir is an investigational medicine, the healthcare team must be aware of the indications, contraindications, mechanism of action, adverse effects, toxicity, and monitoring when managing the care of patients with COVID-19. In addition to the duties mentioned above, all healthcare team members are responsible for educating and counseling patients. Given that nirmatrelvir/ritonavir is the only oral highly-effective antiviral against COVID-19 at this time, judicious use can help curb COVID-19-related morbidity and mortality while minimizing the risk of drug-related adverse events. 

The FDA announced that pharmacists could also prescribe nirmatrelvir/ritonavir; however, patients are required to bring health records(<1 year old), with reports of liver and kidney function along with a comprehensive(including OTC) list of all medications, so the pharmacist can screen for potentially serious drug interactions and check for prescribing eligibility. The FDA has recommended that the pharmacist refer the patient to a physician, advanced practice nurse, or physician assistant if the above criteria are not met.

Consequently, the interprofessional approach with excellent communication between physicians, advanced practice nurses, physician assistants, pharmacists, and specialists are required to accomplish optimal outcomes for nirmatrelvir/ritonavir therapy in patients with COVID-19. This includes meticulous documentation of all interactions and interventions with the patient so that all team members have the same patient data from which to make decisions regarding care.[36] [Level 5]

Finally, genetic sequencing of patients treated with nirmatrelvir/ritonavir is crucial due to the potential for antiviral resistance to SARS-CoV-2.[17] Antiviral stewardship is vital, and antivirals, including nirmatrelvir/ritonavir, should be used judiciously.[38]