Wednesday 01 March 2023
Ensitrelvir (Xocova®) is now included in the list of COVID therapies. Ensitrelvir is an oral antiviral agent developed by Shionogi & Co which obtained emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan in November 2022. Ensitrelvir suppresses the replication of SARS-CoV-2 by selectively inhibiting the viral 3CL protease. It is administered once daily for five days (375 mg on day 1 followed by 125 mg on days 2 to 5).
Ensitrelvir is metabolized by multiple CYP enzymes with the major contribution being from CYP3A4/5. Ensitrelvir should not be coadministered with strong inducers of CYP3A4 as this may result in a marked decrease in ensitrelvir concentrations and the loss of virological response and possible resistance. Due to the persisting inducing effect upon discontinuation of an inducer, an alternative COVID-19 treatment should be considered with strong inducers. Based on a PBPK modelling study, coadministration with a moderate inducer was predicted to reduce ensitrelvir exposure by 24% after 5 days of coadministration. This effect is not considered to be clinically relevant but the Japanese product label recommends caution.
Ensitrelvir is considered to be a strong inhibitor of CYP3A4 and its inhibitory effect is predicted to mostly disappear ~10 days after the last dose. Dose modifications for drugs metabolized by CYP3A4 may need to be maintained for 5-10 days after the last dose of ensitrelvir with the timing being dependent on the contribution of CYP3A4 to the overall metabolism of the drug.
Note, ensitrelvir is an investigational drug outside of Japan and has not yet been approved outside of Japan. In addition, the brand name Xocova® has not been approved for use outside of Japan and pertains only to the approved drug in Japan.