Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy
Open accessAbstract
The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The concentrations of VX-661 and VX-770 used for this study fall within the range of VX-661 plasma concentrations and of VX-770 concentrations in the plasma and nasal tissue of CF patients.
“The concentrations of VX-661 and VX-770 used for this study fall within the range of VX-661 plasma concentrations and of VX-770 concentrations in the plasma and nasal tissue of CF patients (34).”
From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [34]
The Results sections report tezacaftor (VX-661) concentrations in plasma and ivacaftor (VX-770) concentrations in plasma and nasal biopsy cells from people with CF. Those measurements provide the cited patient ranges, but our copy does not give the concentrations used in the citing study, so it cannot establish that those concentrations fall within the reported ranges. (LLM, conf=0.78)
Experimental — accuracy not yet measuredChronic treatment with 1 μM VX-770 significantly decreased functional correction by VX-809 in the presence of acute potentiator addition.
“Chronic treatment with 1 μM VX-770, a concentration that is therapeutically reached in respiratory epithelia (34), was reported to significantly decrease the functional correction by VX-809 in the presence of acute potentiator addition (Figure 3, A and B), as observed in CF-HBE (35, 36) and CF-HNE (21).”
From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [34]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Self-citationHeijerman, H. G. M., McKone, E. F., Downey, D. G., Van Braeckel, E., Rowe, S. M., Tullis, E., Mall, M. A., Welter, J. J., Ramsey, B. W., McKee, C. M., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32597-8 · Cited by 1,414 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 20
- [1]Lubamba B, Dhooghe B, Noel S, Leal T. Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clin Biochem 2012; 45(15): 1132– 44. 22698459
- [2]Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. New Engl J Med 2011; 365(18): 1663– 72. 22047557 PMC3230303
- [3]Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Lumacaftor–Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. New Engl J Med 2015; 373(3): 220– 31. 25981758 PMC4764353
- [4]Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, Tezacaftor-Ivacaftor in residual-function heterozygotes with cystic fibrosis. New Engl J Med 2017; 377(21): 2024– 35. 29099333 PMC6472479
- [5]Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. New Engl J Med 2017; 377(21): 2013– 23. 29099344
- [8]Belkhir L, De Laveleye M, Vandercam B, Zech F, Delongie KA, Capron A, Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug-drug interaction. Clin Biochem 2016; 49(7–8): 580– 6. 26742721
- [9]Mitchell C, Roemer E, Nkwopara E, Robbins B, Cory T, Rue T, Correlation between plasma, intracellular, and cervical tissue levels of raltegravir at steady-state dosing in healthy women. Antimicrob Agents Chemother 2014; 58(6): 3360– 5. 24687503 PMC4068472
- [10]Wang T, Zhang T, Meng T, Li Y, Chen L, Yang Q, A strategy for designing voriconazole dosage regimens to prevent invasive pulmonary aspergillosis based on a cellular pharmacokinetics/pharmacodynamics model. J Transl Med 2018; 16(1): 157. 29880050 PMC5992762
- [11]Baroni D, Zegarra-Moran O, Svensson A, Moran O. Direct interaction of a CFTR potentiator and a CFTR corrector with phospholipid bilayers. Eur Biophys J 2014; 43(6–7): 341– 6. 24771136
- [12]Cholon DM, Quinney NL, Fulcher ML, Esther CR Jr, Das J, Dokholyan NV, Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis. Sci Transl Med 2014; 6(246): 246ra96. PMC4272825 25101886
- [13]Csanady L, Torocsik B. Cystic fibrosis drug ivacaftor stimulates cftr channels at picomolar concentrations. Elife 2019; 8. PMC6594753 31205003
- [14]Matthes E, Goepp J, Carlile GW, Luo Y, Dejgaard K, Billet A, Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor). Br J Pharmacol 2016; 173(3): 459– 70. 26492939 PMC4728415
- [15]Schneider EK, Reyes-Ortega F, Wilson JW, Kotsimbos T, Keating D, Li J, Development of HPLC and LC-MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1038: 57– 62. PMC5287569 27792891
- [16]Liddy AM, McLaughlin G, Schmitz S, D’Arcy DM, Barry MG The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers. Br J Clin Pharmacol 2017. PMC5595953 28477428
- [17]Chin S, Hung M, Won A, Wu YS, Ahmadi S, Yang D, Lipophilicity of the cystic fibrosis drug, ivacaftor (VX-770), and its destabilizing effect on the major CF-causing mutation: F508del. Mol Pharmacol 2018; 94(2): 917– 25. 29903751
- [18]Veit G, Avramescu RG, Perdomo D, Phuan PW, Bagdany M, Apaja PM, Some gating potentiators, including VX-770, diminish DeltaF508-cftr functional expression. Sci Transl Med 2014; 6(246): 246ra97. PMC4467693 25101887
- [20]Solomon GM, Hathorne H, Liu B, Raju SV, Reeves G, Acosta EP, Pilot evaluation of ivacaftor for chronic bronchitis. Lancet Respir Med 2016; 4(6): e32– 3. 27185048 PMC4916910
- [22]Vallet CM, Marquez B, Ngabirano E, Lemaire S, Mingeot-Leclercq MP, Tulkens PM, Cellular accumulation of fluoroquinolones is not predictive of their intracellular activity: studies with gemifloxacin, moxifloxacin and ciprofloxacin in a pharmacokinetic/pharmacodynamic model of uninfected and infected macrophages. Int J Antimicrob Agents 2011; 38(3): 249– 56. 21764262
- [23]Devalia JL, Sapsford RJ, Wells CW, Richman P, Davies RJ. Culture and comparison of human bronchial and nasal epithelial cells in vitro. Respir Med 1990; 84(4): 303– 12. 2236758
- [24]Braunstein GM, Zsembery A, Tucker TA, Schwiebert EM. Purinergic signaling underlies CFTR control of human airway epithelial cell volume. J Cyst Fibros 2004; 3(2): 99– 117. 15463893
Cited by
Sorted by citations
Veit, G., Roldan, A., Hancock, M. A., Da Fonte, D. F., Xu, H., Hussein, M., Frenkiel, S., Matouk, E., Velkov, T., & Lukacs, G. L. (2020) · JCI Insight · doi:10.1172/jci.insight.139983 · Cited by 250 · see citing works
- Authors
- Guimbellot, J. S., Ryan, K. J., Anderson, J. D., Liu, Z., Kersh, L., Esther, C. R., Rowe, S. M., & Acosta, E. P.
- Affiliations
- University of Alabama at Birmingham (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Guimbellot, Jennifer S.
- ORCID
- Venue
- Journal of Cystic Fibrosis
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 19
- Issue
- 5
- Pages
- 742-745
- ISSN
- 1569-1993 (ISSN-L)
- PMC
- PMC7706073
- OpenAlex
- W3004738685
- Cited by
- 24
- References
- 2
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 8 · 2021: 4 · 2020: 3
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Cystic Fibrosis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Cystic Fibrosis Foundation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- ivacaftor, CFTR modulators, plasma drug concentration
- MeSH terms
- Aminophenols, Cystic Fibrosis, Epithelial Cells, Feasibility Studies, Humans, Pilot Projects, Quinolones, Chloride Channel Agonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
