Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor

Abstract

Introduction: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) C 12 years of age with C 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC. Methods: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from monoor dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF C 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC 50) estimated from efficacy endpoint data from clinical studies. Results: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and C 1 CFTR corrector remained above EC 50. Conclusion: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor Digital Features To view digital features for this article go to

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

“…It was constructed based on available physicochemical properties and clinical data from published PK studies. 11 , 14 , 15 , 16 , 17 The in vitro studies and clinical DDI data suggest that ivacaftor is predominantly eliminated through CYP3A4‐mediated hepatic metabolism. 13 Therefore, the excretion was set to enzyme kinetics to quantify its metabolism by CYP3A.…”

PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19

“…For the PBPK model of ivacaftor, in the absence of an in vitro estimate, clinical interaction data with strong modulators of CYP3A4 were used to assign fmCYP3A4. First, we predicted DDI with ketoconazole by varying the fmCYP3A4 value of ivacaftor from 95% to 100% ( Figure S1A ), since it has been reported that the fractional metabolism of ivacaftor assigned to CYP3A4 is greater than 95%(17). An fmCYP3A4 of 98 % predicted the AUC ratio (GMR 6.95) of ivacaftor within the bioequivalence limit (80-125%) of the observed AUC ratio (GMR 8.45).…”

“…al. published a ETI PBPK model to evaluate exposures during the transition from mono or dual combination of CFTR modulators to ETI(17). We extended the models by refining the ivacaftor model and further validating the ETI PBPK-DDI model with published clinical DDI data.…”

“…The tezacaftor and elexacaftor PBPK models were constructed based on the data from the PBPK review section within the NDA documents and the publication of Tsai et al(12, 13, 17). Briefly, the elexacaftor and tezacaftor models consist of the first-order absorption and a minimal PBPK model.…”

“…The minimal PBPK model consists of no more than five compartments, that include the gastrointestinal tract, blood, liver, and up to two additional compartments, reducing the complexity of the model while allowing for mechanistic simulations in the compartment of interest (15). The ivacaftor model was constructed based on available physicochemical properties and clinical data from published PK studies (11,(16)(17)(18)(19).…”