Cystic fibrosis (CF) patients with moderate hepatic impairment should be given a lower dose of the combination therapy elexacaftor/tezacaftor/ivacaftor (Trikafta®), according to a study published in the European Journal of Drug Metabolism and Pharmacokinetics.

During the phase 1 study, participants without CF but with moderately reduced liver function had significantly higher levels of the drugs elexacaftor, tezacaftor, and ivacaftor in their bodies than healthy controls after receiving the combination treatment for 10 days.

“Based on these findings, treatment with elexacaftor/tezacaftor/ivacaftor should be modified in [people with CF] with moderate hepatic impairment according to the prescribing information,” the authors said.

The area under the curve during the dosing interval (AUCτ) of elexacaftor was 1.25-fold (90% CI, 1.01-1.54) higher in participants with hepatic impairment than in healthy controls. Levels of the major metabolite M23-elexacaftor were increased 1.73-fold (90% CI, 1.27-2.35) in those with hepatic impairment.

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Participants with hepatic impairment also had increased mean AUCτ values for ivacaftor (1.50-fold; 90% CI, 1.09-2.06) and tezacaftor (1.20-fold; 90% CI, 1.00-1.43). In contrast, the mean value of the tezacaftor metabolite M1-tezacaftor was 1.29-fold lower (90% CI, 0.655-0.924) in those with hepatic impairment.

The authors attributed the decrease in M1-tezacaftor to the reduced ability of participants with hepatic impairment to metabolize tezacaftor. The increase in the elexacaftor metabolite M23-elexacaftor may be due to it not being the terminal metabolite, and hepatic impairment may reduce the participant’s ability to break it down further.

Twenty-two participants were enrolled in the study, including 11 healthy controls and 11 participants with moderate hepatic impairment from sites in the Czech Republic and Slovakia. All participants were White, and 81.8% (n=18) were male. Participants received 50% of the recommended dose for patients with CF for 10 days.


Viswanathan L, Bachman E, Tian S, et al. Phase 1 study to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in subjects without cystic fibrosis with moderate hepatic impairment. Eur J Drug Metab Pharmacokinet. Published online August 29, 2022. doi:10.1007/s13318-022-00791-8