In primary G551D/F508del bronchial epithelia from one donor, VX-770 increased forskolin-stimulated chloride secretion to 48 ± 4% of the non-CF comparator response. Uncorrected F508del-homozygous cultures responded variably: significant potentiation occurred in three of six donors. [1]
Chronic exposure depended on genotype and assay context. At 5 μM for 48 h, VX-770 preserved the total stimulated response in G551D/F508del HBE, but reduced VX-809-rescued function in F508del/F508del HBE. In a separate study, 100 nM VX-770 for 24 h did not reduce function under moderate potentiation, while a 10 μM acute challenge revealed inhibition. Albumin during pretreatment prevented inhibition by the micromolar combination. [2,3]
Potentiation of activated CFTR in excised membrane patches
Cell-based study · Inside-out patches from G551D-CFTR FRT cells and wild-type/F508del-CFTR NIH 3T3 cells; F508del cells temperature-rescued at 27 °C for 24 h. [1]
VX-770 increased channel open probability after PKA/ATP activation. This supports an action on channel gating; it does not by itself locate a binding site.
Literature-Reported Treatment Conditions
- Treatment concentration
- 10 μM for G551D; 1 μM for F508del and wild-type CFTR
- Exposure duration
- Acute application during recording; exact exposure interval not specified in the adopted main-text locations.
- Method
- Excised inside-out patch clamp; agents applied to the cytoplasmic face.
- Vehicle
- Not specified for these recordings in the retrieved main text.
- Co-treatment
- PKA 75 nM and ATP 1 mM present before VX-770.
- Reported limits
- Detailed SI recording solutions and patch vehicle were not retrieved.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results sec2 (final paragraph); Fig. 2A–C and caption; Methods sec10
Change in open probability relative to PKA/ATP alone: Recording before/during drug; Fig. 2C reports n = 5–6 and P < 0.05 (t test); means/SEM per main statistical methods. — Results sec2, final paragraph; Fig. 2C and caption; sec12
Acute chloride secretion in primary CF airway epithelia
Cell-based study · Primary human bronchial epithelia: one G551D/F508del donor, six F508del-homozygous donors; non-CF comparator cultures from four donors. [1]
VX-770 enhanced stimulated chloride secretion strongly in the G551D/F508del culture. Only three of six uncorrected F508del-homozygous donor cultures showed significant potentiation.
Literature-Reported Treatment Conditions
- Treatment concentration
- Concentration–response; representative recordings extend to 10 μM VX-770.
- Exposure duration
- Acute sequential additions in Ussing recordings; exact equilibration time not specified in the main text.
- Method
- Voltage-clamped transepithelial current with basolateral-to-apical chloride gradient; amiloride 30 μM, forskolin 10 μM; CFTRinh-172 20 μM inhibition control.
- Vehicle
- Not specified for this experiment in the retrieved main-text locations.
- Co-treatment
- Forskolin stimulation; no corrector or temperature rescue of primary F508del cultures.
- Reported limits
- Full SI culture/recording details not retrieved. n values below are culture/recording counts, not independent donor counts.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results sec3; Fig. 3A–D and caption; Methods sec7–sec8, sec12
VX-770 potentiation of forskolin-stimulated transepithelial current in G551D/F508del HBE: Concentration–response in a single donor culture; reported mean ± SEM. This is assay potency, not a treatment dose. — Results sec3, first results paragraph; Fig. 3B; sec12
Maximal stimulated current in G551D/F508del HBE: Approximate tenfold enhancement; forskolin-only baseline 2.9 ± 0.5 μA/cm². Mean ± SEM; CFTR inhibitor blocked response. — Results sec3; Fig. 3A–B
Response of uncorrected F508del-homozygous HBE: No effort to correct trafficking; potency/maximum apply to responders, not all six donors. Fig. 3B reports n = 7–24 for responder curves; Fig. 3C n = 4–24. Values are mean ± SEM. — Results sec3, final paragraph; Fig. 3B–D and caption
Acute versus chronic exposure in G551D/F508del HBE
Cell-based study · Differentiated primary G551D/F508del HBE from three patients; 3–4 replicates per patient, 10 measurements per treatment. [2]
Chronic VX-770 increased forskolin responsiveness and reduced the incremental response to acute VX-770. Total stimulated CFTR response was comparable with the acutely potentiated vehicle-pretreated cultures.
Literature-Reported Treatment Conditions
- Treatment concentration
- 5 μM VX-770 during pretreatment; 5 μM acute VX-770 challenge
- Exposure duration
- 48 h pretreatment, followed by acute Ussing assay.
- Method
- Basolateral pretreatment; Ussing chamber assay with amiloride 100 μM, forskolin 10 μM, then acute VX-770 and CFTRinh-172 10 μM.
- Vehicle
- 0.1% DMSO comparator.
- Co-treatment
- No corrector; forskolin stimulation during functional assay.
- Reported limits
- Exact acute exposure interval is not specified in the adopted text.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results S3; Fig. 1A–E and caption; Methods S12–S13, S17, S20
Chronic versus vehicle pretreatment: forskolin and incremental acute-potentiator responses: Fig. 1B–E; source states statistics use donor-average responses and SEM; 10 measurements are not 10 independent patients. — Results S3; Fig. 1B–E and caption; Methods S20
Chronic VX-770 attenuates VX-809 rescue of F508del HBE
Cell-based study · Primary F508del/F508del HBE from six patients; 2–4 replicates per patient, 15 measurements per condition. [2]
Co-exposure to VX-770 and VX-809 reduced stimulated chloride-secretory responses relative to VX-809 alone under this 48 h micromolar protocol. Acute VX-770 potentiation after corrector-only pretreatment had the opposite direction.
Literature-Reported Treatment Conditions
- Treatment concentration
- VX-809 5 μM with or without VX-770 5 μM; acute assay VX-770 5 μM
- Exposure duration
- 48 h pretreatment followed by acute assay.
- Method
- Primary ALI cultures at 37 °C; Ussing recordings with chloride gradient, amiloride 100 μM, forskolin 10 μM, acute VX-770 and CFTRinh-172 10 μM.
- Vehicle
- DMSO comparator; concentration not specified in Fig. 2 caption.
- Co-treatment
- VX-809 corrector; result is a combination comparison, not VX-770 monotherapy.
- Reported limits
- SI numerical tables not retrieved; no exact current magnitudes inferred from bars.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results S4; Fig. 2A–D and caption; Methods S12–S13, S17, S20
Chronic combination versus corrector-only pretreatment: Versus VX-809 alone; source uses donor-average responses and SEM. Acute VX-770 response after VX-809 alone exceeded vehicle (P = 0.0177). — Results S4; Fig. 2B–D and caption; Methods S20
Chronic low-concentration exposure and acute assay dependence
Cell-based study · Well-differentiated F508del/F508del primary HBE; three donor cultures compared in Fig. 3A; high-challenge HBE comparison in Fig. 3C–D. [3]
With 100 nM VX-770 pretreatment, no functional reduction was observed using moderate potentiation. A 10 μM acute VX-770 challenge revealed an inhibitory difference. Thus the assay challenge changes the apparent chronic-exposure result.
Literature-Reported Treatment Conditions
- Treatment concentration
- Core comparison: VX-809 1 μM with/without VX-770 100 nM during pretreatment; Fig. 2C also tests chronic VX-770 1 nM–10 μM with VX-809 1 μM. Acute VX-770 challenge 100 nM or 10 μM as specified by assay.
- Exposure duration
- 24 h pretreatment; acute assay afterward.
- Method
- Ussing short-circuit current; chloride gradient; forskolin 10 μM; genistein 50 μM or acute VX-770 for potentiation; CFTRinh-172 10 μM. High-challenge protocol adds VX-770 10 μM before forskolin.
- Vehicle
- 0.1% DMSO.
- Co-treatment
- VX-809 corrector required; forskolin and specified potentiator challenge during assay.
- Reported limits
- n = 3 in Fig. 3D is reported as observations, not established as three independent donors for that particular comparison.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results sec0016–sec0017; Fig. 2A–C, Fig. 3A–D and captions; Methods sec0008–sec0009, sec0012–sec0013
Functional response after chronic 100 nM VX-770 + VX-809 versus corrector alone with moderate acute potentiation: Fig. 2 reports means ± SEM, n = 3–4; Fig. 3A checks cultures from three patients. Endpoint is functional current, not channel surface density. — Results sec0016; Fig. 2B–C; Fig. 3A and captions
Current response to acute VX-770 10 μM + forskolin after corrector-only versus combination pretreatment: First value: VX-809 pretreatment; second: VX-809 + 100 nM VX-770 pretreatment. Both challenged acutely with 10 μM VX-770 and 10 μM forskolin. — Results sec0017; Fig. 3C–D and caption
Albumin changes the response to chronic micromolar VX-770
Cell-based study · Primary F508del/F508del HBE exposed to VX-809/VX-770 in the presence or absence of BSA. [3]
The inhibitory response at 5 μM VX-770 with 5 μM VX-809 was prevented by albumin during pretreatment. This supports protein-context dependence without establishing airway free drug concentrations in vivo.
Literature-Reported Treatment Conditions
- Treatment concentration
- VX-770 5 μM + VX-809 5 μM; BSA 40 or 20 mg·mL⁻¹; low-concentration reference: VX-770 100 nM + VX-809 1 μM
- Exposure duration
- 24 h pretreatment followed by functional assay.
- Method
- Ussing current response to forskolin 10 μM; genistein 50 μM potentiates corrector-only controls; CFTRinh-172 10 μM.
- Vehicle
- 0.1% DMSO.
- Co-treatment
- VX-809 combination; albumin present during pretreatment.
- Reported limits
- Fig. 4 axes normalize responses to non-CF HBE, whereas Results sec0019 labels example values as current density. Numerical magnitudes and those units are withheld because this discrepancy is unresolved.
Methods and source locations
Compound reported in the paper: Ivacaftor (VX-770); Compound label in the paper: VX-770
Evidence concerns the reported research compound and model; it does not establish performance of an Adooq lot.
Results sec0019; Fig. 4A–D and caption; Methods sec0009, sec0012–sec0013
Effect of albumin on inhibitory response to chronic micromolar combination: Direction supported by Fig. 4B,D and caption; B reports n = 5–6, C–D n = 3; error bars are SEM. No numerical ordinate magnitudes adopted. — Results sec0019; Fig. 4A–D and caption
