Pharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor

Garg, Varun; Shen, Jim X.; Li, Chonghua; Agarwal, Sagar; Gebre, Asfiha; Robertson, Sarah; Huang, Jinzhou; Han, Linda; Jiang, Licong; Stephan, Kristin; Wang, Linda T.; Lekstrom-Himes, Julie

doi:10.1111/cts.12610

Cited by 25 publications

(23 citation statements)

References 3 publications

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“…Reports suggest that lumafctor may be an inducer of cytochrome (CYP) drug metabolizing enzymes 29,34,35. Lumacaftor being an inducer of CYP3A4 and ivacaftor being a substrate, a clinically significant interaction between the two drugs is possible.…”

Section: Results and Analysismentioning

confidence: 99%

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<p>Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis</p>

Shiferaw¹,

Faruqi²

2019

TCRM

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Cystic fibrosis (CF) is a life-limiting autosomal recessive disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Management of CF has traditionally relied upon managing complications of CFTR protein dysfunction and this has led to a steady improvement in survival of CF patients. However, the landscape of CF care has changed substantially over the last decade with the discovery of CFTR modulators that aim to increase or potentially restore the function of the disease-causing CFTR protein. This narrative review summarizes the development of CFTR therapies so far with emphasis on tezacaftor/ivacaftor combination therapy. We have also summarized the Phase II results of triple combination therapy which promises an effective CFTR modulator therapy for more than 90% of CF patients.

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Section: Results and Analysismentioning

confidence: 99%

“…However, tezacaftor is not an inducer of CYP3A4 enzymes which makes drug–drug interactions of less concern. It has been demonstrated that the metabolism of drugs which are CYP3A substrates, including hormonal contraceptives, is unlikely to be affected by tezacaftor/ivacaftor combination therapy 35…”

Section: Results and Analysismentioning

confidence: 99%

<p>Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis</p>

Shiferaw¹,

Faruqi²

2019

TCRM

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“…Our data further validate this decision, showing an additive effect of combined VX-809 and VX-770. Of note, VX-661 (tezacaftor) is derived from corrector VX-809, and was developed to reduce drug-drug interactions with VX-770 [39]. Its mode of action, however, is similar.…”

Section: Discussionmentioning

confidence: 99%

Phenotyping of Rare CFTR Mutations Reveals Distinct Trafficking and Functional Defects

Ensinck

Keersmaecker

Heylen

et al. 2020

Cells

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Background. The most common CFTR mutation, F508del, presents with multiple cellular defects. However, the possible multiple defects caused by many rarer CFTR mutations are not well studied. We investigated four rare CFTR mutations E60K, G85E, E92K and A455E against well-characterized mutations, F508del and G551D, and their responses to corrector VX-809 and/or potentiator VX-770. Methods. Using complementary assays in HEK293T stable cell lines, we determined maturation by Western blotting, trafficking by flow cytometry using extracellular 3HA-tagged CFTR, and function by halide-sensitive YFP quenching. In the forskolin-induced swelling assay in intestinal organoids, we validated the effect of tagged versus endogenous CFTR. Results. Treatment with VX-809 significantly restored maturation, PM localization and function of both E60K and E92K. Mechanistically, VX-809 not only raised the total amount of CFTR, but significantly increased the traffic efficiency, which was not the case for A455E. G85E was refractory to VX-809 and VX-770 treatment. Conclusions. Since no single model or assay allows deciphering all defects at once, we propose a combination of phenotypic assays to collect rapid and early insights into the multiple defects of CFTR variants.

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“…Nevertheless, as CF patients are already subjected to a substantial burden of medications, drug-drug interaction profiles should be further exploited to avoid adverse effects or inhibitory effects of one therapy on another. In this line, itraconazole, an antifungal commonly used for the treatment of allergic bronchopulmonary aspergillosis, was demonstrated to significantly increase systemic exposures of tezacaftor and ivacaftor (Garg et al, 2019). Caution and appropriate monitoring are recommended when these therapies are used at the same period.…”

Section: Continuing the Development Of Transformative Therapeutics Tomentioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Pharmacokinetic and Drug–Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor

Cited by 25 publications

References 3 publications

<p>Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis</p>

<p>Profile of tezacaftor/ivacaftor combination and its potential in the treatment of cystic fibrosis</p>

Phenotyping of Rare CFTR Mutations Reveals Distinct Trafficking and Functional Defects

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

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