Physiologically Based Pharmacokinetic Modeling of Elexacaftor/Tezacaftor/Ivacaftor in Infants With Cystic Fibrosis.

Abstract

Ivacaftor is the only cystic fibrosis transmembrane conductance regulator modulator approved for infants ≥ 1 month. The elexacaftor/tezacaftor/ivacaftor combination, approved for children aged ≥ 2 years, has been shown to significantly slow CF progression. Expanding elexacaftor/tezacaftor/ivacaftor use to infants may offer additional therapeutic benefits. This study aims to predict elexacaftor/tezacaftor/ivacaftor pharmacokinetics in infants aged 1 month to < 2 years using physiologically based pharmacokinetic modeling (PBPK) and to determine whether age- and weight elexacaftor/tezacaftor/ivacaftor doses, extrapolated from ivacaftor monotherapy, produce drug exposures comparable to adult levels. Adult elexacaftor/tezacaftor/ivacaftor PBPK published models were first reproduced using Simcyp. These models were scaled to children aged 2-18 years via the Simcyp Pediatric Simulator and the Uprety-Wahlström cytochrome-P450 3A4 ontogeny method to simulate the current elexacaftor/tezacaftor/ivacaftor dosing regimen. FDA-approved ivacaftor monotherapy dosing was evaluated in children 1 month to < 2 years and subsequently used to guide the extrapolation of elexacaftor/tezacaftor/ivacaftor combination dosing regimens. The overall workflow was validated using in vivo pharmacokinetic data or literature-based sources. Elexacaftor/tezacaftor/ivacaftor PBPK models for adults and children ≥ 2 years were validated against observed clinical pharmacokinetic data. Simulations of elexacaftor/tezacaftor/ivacaftor doses based on ivacaftor monotherapy in infants < 2 years matched adult-reported levels, except in infants 1-2 months, who showed lower exposures, and in those weighing ≥ 14 kg, who may experience higher exposures. Using PBPK modeling, supported by clinical pharmacokinetic data, this study explores elexacaftor/tezacaftor/ivacaftor dosing in children under 2 years. The findings offer preliminary dosing guidance, pending confirmation in larger clinical studies, with therapeutic drug monitoring recommended to guide treatment.