Dear Sir,Three antiviral agents (remdesivir, molnupiravir, and nirmatrelvir) have gained prominence for community‐based early management of proven COVID‐19 infection.
Nirmatrelvir acts via inhibition of the SARS‐CoV‐2 main protease (Mpro), also referred to as 3C‐like protease (3CLpro) or nsp5 protease, which is essential for viral replication. Nirmatrelvir is combined with a protease inhibitor, ritonavir, that slows the metabolism of nirmatrelvir via cytochrome enzyme inhibition. Ritonavir is a strong inhibitor of CYP3A but has lesser effect on other CYP isoenzymes, for example, 2D6, 2B6, and 2C9. A large number of medicines are metabolized by CYP3A, and therefore, that the inclusion of ritonavir in the drug combination is likely to create complexities and restrictions in its use.Future widespread community use of oral nirmatrelvir/ritonavir (Paxlovid®) has implications for those responsible for anesthesia delivery to children. The inhibition of CYP3A enzyme by ritonavir may impair the metabolism of frequently used anesthetic and analgesic drugs such as midazolam, fentanyl, alfentanil, ketamine, rocuronium, and bupivacaine.
Clearance will be reduced and plasma concentration slow to decrease. Clinical implications will depend on how the anesthetic drug is administered (single bolus only or via infusion or repeated boluses); infusion, for example, will result in a higher steady‐state concentration when clearance is reduced, plasma concentration decreases may be dictated more by redistribution than metabolism. The activity of alternative clearance pathways beside CYP3A and the concentration‐response relationship for any particular drug will also have impact on any observed effect.It currently remains unclear whether the use of this antiviral drug will lead to a clinically significant change in response to an individual drug; however, co‐administration of these anesthetic drugs with nirmatrelvir/ritonavir may require dosage adjustment and monitoring of therapeutic and adverse effects, particularly in high‐risk cases.Children who present for anesthesia are often taking medications for concomitant pathology. For example, co‐administration of ritonavir with medications such as carbamazepine can lead to both a risk of toxicity from an increased concentration of the anticonvulsant, as well as a potential loss of virological response because of a competitive interaction. The inhibitory effect of ritonavir on the CYP3A4 enzyme is predicted to mostly disappear approximately 3 days after stopping the drug.Indications for the future use of nirmatrelvir/ritonavir remain uncertain. If it is used to treat children that are unvaccinated, then anesthetic practitioners are likely to encounter them as patients, either as part of their treatment for COVID‐19 infection or coincidentally during treatment or investigation of other illnesses. We would urge caution in their management and encourage colleagues to review possible drug interactions.
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Consideration should be given to delaying any interventions until at least 3 days after stopping the antiviral agent.
CONFLICT OF INTEREST
HH has no conflicts of interest to declare. BJA is an Associate Editor‐in‐Chief for Pediatric Anesthesia.
Funding information
This work was funded from institutional resources.