Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono
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ORIGINAL RESEARCH
Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to TripleCombination Elexacaftor/Tezacaftor/Ivacaftor Alice Tsai
. Shu-Pei Wu . Eric Haseltine . Sanjeev Kumar .
Samuel M. Moskowitz . Paul Panorchan . Kushal Shah
Received: June 18, 2020 Ó The Author(s) 2020
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 Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12666467. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s41030020-00124-7) contains supplementary material, which is available to authorized users. A. Tsai (&) S.-P. Wu E. Haseltine S. Kumar S. M. Moskowitz P. Panorchan K. Shah Vertex Pharmaceuticals Incorporated, Boston, MA, USA e-mail: [email protected]
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 (EC50) 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 EC50. Conclusion: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/
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