Physiologically‐Based Pharmacokinetic‐Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor‐Tezacaftor‐Ivacaftor With Nirmatrelvir‐Ritonavir for the Treatment of COVID‐19

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor‐tezacaftor‐ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A–mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID‐19) with nirmatrelvir‐ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug–drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID‐19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A‐mediated DDI of elexacaftor‐tezacaftor‐ivacaftor was evaluated using a physiologically‐based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug‐dependent parameters of elexacaftor‐tezacaftor‐ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor‐tezacaftor‐ivacaftor. The elexacaftor‐tezacaftor‐ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor‐tezacaftor‐ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor‐tezacaftor‐ivacaftor should be reduced when coadministered with nirmatrelvir‐ritonavir to elexacaftor 200 mg–tezacaftor 100 mg–ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full‐dose elexacaftor‐tezacaftor‐ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism‐based inhibitor. The simulation predicts a regimen of elexacaftor‐tezacaftor‐ivacaftor administered concomitantly with nirmatrelvir‐ritonavir in people with CF that will likely decrease the impact of the drug interaction.