Entry of cystic fibrosis transmembrane conductance potentiator ivacaftor into the developing brain and lung.

BACKGROUND: The potential effects of ivacaftor during pregnancy and breastfeeding on the offspring are still unknown. This study aimed to investigate pre-/postnatal age-related entry into the brain and lungs and transfer of maternally administered drug by the placental and via the milk. METHODS: In acute experiments Sprague Dawley rats at embryonic day (E) 19, postnatal days (P) 4, 9, 16, and adult were administered an intraperitoneal injection of ivacaftor (40 mg/kg) traced with [3H] ivacaftor. To determine tissue entry, plasma, cerebrospinal fluid (CSF), lungs and brains were collected, and radioactivity measured using liquid scintillation counting. For long term experiments pregnant dams were orally treated at 25 mg/kg/day for 7 days and pups collected at E19. For postnatal pups, dams received treatment for 7 or 14 days and pups were collected at P6, 9, 13 and 16. To estimate placental and milk transfer concentration of ivacaftor in pup & maternal plasma was determined by liquid chromatography-mass spectrometry. RESULTS: At all ages, entry of ivacaftor into lungs, following either acute or prolonged exposure, was much higher than into brain & CSF. Brain entry appeared higher at earlier ages. Transfer across the placenta and breast milk. was estimated to be around ~40% of maternal plasma. CONCLUSIONS: Fetal and postnatal rats were exposed to maternally administered ivacaftor via placental and milk transfer. Preferential entry in the lungs at all ages suggests the possibility that exposing CF babies to maternally administered ivacaftor could be beneficial for limiting progression of CF pathology in early development.

Pharmacokinetic interactions between ivacaftor and cytochrome P450 3A4 inhibitors in people with cystic fibrosis and healthy controls.

BACKGROUND: Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF. METHODS: A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor. RESULTS: We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times. CONCLUSION: Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

Quantitative Method for the Analysis of Ivacaftor, Hydroxymethyl Ivacaftor, Ivacaftor Carboxylate, Lumacaftor, and Tezacaftor in Plasma and Sputum Using Liquid Chromatography With Tandem Mass Spectrometry and Its Clinical Applicability.

BACKGROUND: The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry. METHODS: The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample. Liquid chromatography with tandem mass spectrometry was performed for a total run time of 6 minutes. The method was validated by assessing selectivity, carryover, linearity, accuracy and precision, dilution, matrix effects, and stability. RESULTS: The selectivity was good as no interference from matrices was observed. In the concentration range from 0.01 to 10.0 mg/L, calibration curves were linear with a correlation coefficient >0.9997 for all compounds. The within-run and between-run accuracy were between 99.7% and 116% at the lower limit of quantitation (LLOQ) and between 95.8% and 112.9% for all concentrations above LLOQ for all analytes in plasma and sputum. Within-run and between-run precisions were <12.7% for LLOQ and <6.7% for the higher limit of quantitation. Samples were stable, with no significant degradation at examined temperatures and time points. Clinical applicability was revealed by analyzing samples from 2 patients with CF. CONCLUSIONS: The presented method enables simultaneous quantification of ivacaftor, lumacaftor, and tezacaftor in plasma and sputum and is an improvement over previous methods because it uses smaller sample volumes, a simple pretreatment protocol, and includes tezacaftor. In future studies, it can be applied for examining pharmacokinetics characteristics of new CF transmembrane conductance regulator modulators.

Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial.

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.

BACKGROUND: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. METHODS: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with ivacaftor plus lumacaftor or ivacaftor plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. RESULTS: During treatment, ivacaftor accumulated in CF-HBEs to a much greater extent than either lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further ivacaftor accumulation, though remained above baseline even after washout. CONCLUSIONS: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches.

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation.

BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.

Human metabolism and urinary excretion kinetics of the UV filter Uvinul A plus® after a single oral or dermal dosage.

Hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, better known under its trading name Uvinul A plus® is a UV filter mainly used in sunscreens, but also present in other cosmetic products with a maximum concentration of 10% (w/w) according to the EU directive. In this study we investigated the human metabolism after a single oral and a single dermal dose of Uvinul A plus®, respectively. Samples collected within 72 h of administration were analyzed with a newly developed UHPLC-MS/MS method. Results of the study revealed three major urinary metabolites, namely 2-(4-amino-2-hydroxybenzoyl)benzoic acid (AHB), 2-(4-(ethylamino)-2-hydroxybenzoyl)benzoic acid (EHB) and 2-(4-(diethylamino)-2-hydroxybenzoyl)benzoic acid (DHB), representing 52% of the administered oral dose. The three major metabolites are further converted into four minor metabolites with an additional hydroxyl group in the aniline moiety. Toxicokinetic parameters (amount excreted, tmax, elimination constant and half-life t1/2) and conversion factors were determined for the three major metabolites. The conversion factors were used to estimate the mean daily exposure to Uvinul A plus® in spot urine samples from 58 volunteers not intentionally exposed to Uvinul A plus® derived from a pilot study. The three major metabolites were quantifiable in 26% of the samples. In 35% of the samples, at least one major metabolite could be quantified. The daily systemic exposure to Uvinul A plus® was estimated to approximately 8.1-9.3 µg/d by applying the combined conversion factor for all three major metabolites. In conclusion, a very low systemic exposure to DHHB was observed with regard to the no observed adverse effect level (NOAEL) as an established threshold for chronic uptake.

Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy.

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.

Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response. METHODS: Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses. RESULTS: We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug. CONCLUSIONS: Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.

GLPG2737 in lumacaftor/ivacaftor-treated CF subjects homozygous for the F508del mutation: A randomized phase 2A trial (PELICAN).

BACKGROUND: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400mg/ivacaftor 250mg for ≥12weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. RESULTS: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75mg; n=14) or placebo (n=8) capsules twice daily for 28days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference-19.6mmol/L [95% confidence interval (CI) -36.0, -3.2], p=.0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI -0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected. CONCLUSIONS: GLPG2737 was well tolerated and yielded significant decreases in sweat chloride concentration versus placebo in subjects homozygous for F508del receiving lumacaftor/ivacaftor, demonstrating evidence of increased CFTR activity when added to a potentiator-corrector combination. FUNDING: Galapagos NV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03474042.

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

BACKGROUND: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations. METHODS: Part A informed weight-based tezacaftor/ivacaftor dosages for part B. The primary objective of part B was to evaluate the safety and tolerability of tezacaftor/ivacaftor through 24 weeks; the secondary objective was to evaluate efficacy based on changes from baseline in percentage predicted forced expiratory volume in 1 s (ppFEV1), growth parameters, sweat chloride, and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: After PK analysis in part A, 70 children received ≥1 dose of tezacaftor/ivacaftor in part B; 67 children completed treatment. Exposures in children aged 6 through 11 years were within the target range for those observed in patients aged ≥12 years. The safety profile of tezacaftor/ivacaftor was generally similar to prior studies in patients aged ≥12 years. One child discontinued treatment for a serious adverse event of constipation. Tezacaftor/ivacaftor treatment improved sweat chloride levels and CFQ-R respiratory domain scores, mean ppFEV1 remained stable in the normal range, and growth parameters remained stable over 24 weeks. CONCLUSIONS: Tezacaftor/ivacaftor was generally safe and well tolerated, and improved CFTR function in children aged 6 through 11 years with CF with F/F and F/RF genotypes, supporting tezacaftor/ivacaftor use in this age group. NCT02953314.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.

Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study.

BACKGROUND: The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years. METHODS: In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132. FINDINGS: The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24. INTERPRETATION: Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease. FUNDING: Vertex Pharmaceuticals Incorporated.

Predictive factors for lumacaftor/ivacaftor clinical response.

BACKGROUND: Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy. METHODS: Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. ß-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched. RESULTS: Sweat chloride concentration significantly decreased after treatment, whereas the ß-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect. CONCLUSION: This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.

IVACAFTOR restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation.

OBJECTIVE: Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients. METHODS: In CF patients with an S1251N mutation (N = 16; age 9-35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10-24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor. RESULTS: At baseline, median FGF19 was lower (52% and 53%, P < .001) and median C4 higher (350% and 364%, P < .001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function. CONCLUSIONS: We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs.

Measured fetal and neonatal exposure to Lumacaftor and Ivacaftor during pregnancy and while breastfeeding.

With the growing class of CFTR modulator therapy available to more patients and with increasing pregnancies in individuals with CF, there is a growing need to understand the effects of these agents during pregnancy. There are few reports of their continued use in the literature, although it is likely that this is not an uncommon occurrence. We report the uncomplicated and successful pregnancy of a woman treated with lumacaftor/ivacaftor, as well as the clinical course of the infant during the first 9 months of life. We also report drug levels in plasma from the mother, cord blood, breast milk, and infant to estimate fetal and infant drug exposure.

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients.

BACKGROUND: This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. METHODS: Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. RESULTS: Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. CONCLUSIONS: We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction.