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Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients

Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk...

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Detalles Bibliográficos
Autores principales: Hong, Eunjin, Carmanov, Eugeniu, Shi, Alan, Chung, Peter S., Rao, Adupa P., Forrester, Kevin, Beringer, Paul M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222456/
https://www.ncbi.nlm.nih.gov/pubmed/37242680
http://dx.doi.org/10.3390/pharmaceutics15051438
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author Hong, Eunjin
Carmanov, Eugeniu
Shi, Alan
Chung, Peter S.
Rao, Adupa P.
Forrester, Kevin
Beringer, Paul M.
author_facet Hong, Eunjin
Carmanov, Eugeniu
Shi, Alan
Chung, Peter S.
Rao, Adupa P.
Forrester, Kevin
Beringer, Paul M.
author_sort Hong, Eunjin
collection PubMed
description Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug–drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor–tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus. To further support the findings in PBPK modeling, we present a case series of lung transplant patients who received both ETI and tacrolimus. We predicted a 2.36-fold increase in tacrolimus exposure when co-administered with ivacaftor, which would require a 50% dose reduction of tacrolimus upon initiation of ETI treatment to avoid the risk of elevated systemic exposure. Clinical cases (N = 13) indicate a median 32% (IQR: −14.30, 63.80) increase in the dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) after starting ETI. These results indicate that the concomitant administration of tacrolimus and ETI may lead to a clinically significant DDI, requiring the dose adjustment of tacrolimus.
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spelling pubmed-102224562023-05-28 Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients Hong, Eunjin Carmanov, Eugeniu Shi, Alan Chung, Peter S. Rao, Adupa P. Forrester, Kevin Beringer, Paul M. Pharmaceutics Article Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug–drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor–tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus. To further support the findings in PBPK modeling, we present a case series of lung transplant patients who received both ETI and tacrolimus. We predicted a 2.36-fold increase in tacrolimus exposure when co-administered with ivacaftor, which would require a 50% dose reduction of tacrolimus upon initiation of ETI treatment to avoid the risk of elevated systemic exposure. Clinical cases (N = 13) indicate a median 32% (IQR: −14.30, 63.80) increase in the dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) after starting ETI. These results indicate that the concomitant administration of tacrolimus and ETI may lead to a clinically significant DDI, requiring the dose adjustment of tacrolimus. MDPI 2023-05-08 /pmc/articles/PMC10222456/ /pubmed/37242680 http://dx.doi.org/10.3390/pharmaceutics15051438 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hong, Eunjin
Carmanov, Eugeniu
Shi, Alan
Chung, Peter S.
Rao, Adupa P.
Forrester, Kevin
Beringer, Paul M.
Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title_full Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title_fullStr Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title_full_unstemmed Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title_short Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions between Elexacaftor/Tezacaftor/Ivacaftor and Tacrolimus in Lung Transplant Recipients
title_sort application of physiologically based pharmacokinetic modeling to predict drug–drug interactions between elexacaftor/tezacaftor/ivacaftor and tacrolimus in lung transplant recipients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10222456/
https://www.ncbi.nlm.nih.gov/pubmed/37242680
http://dx.doi.org/10.3390/pharmaceutics15051438
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