Icenticaftor, a CFTR Potentiator, in COPD: A Multicenter, Parallel-Group, Double-Blind Clinical Trial.

Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction is associated with mucus accumulation and worsening chronic obstructive pulmonary disease (COPD) symptoms. Objectives: The aim of this phase IIb dose-finding study was to compare a CFTR potentiator, icenticaftor (QBW251), with placebo in patients with COPD and chronic bronchitis. Methods: Patients with COPD on triple therapy for at least three months were randomized to six treatment arms (icenticaftor 450, 300, 150, 75, or 25 mg or placebo twice daily [b.i.d.]) in a 24-week, multicenter, parallel-group, double-blind study. The primary endpoint was change from baseline in trough FEV1 after 12 weeks. Secondary endpoints included change from baseline in trough FEV1 and Evaluating Respiratory Symptoms in COPD (E-RS) total and cough and sputum scores after 24 weeks. Multiple comparison procedure-modeling was conducted to characterize dose-response relationship. Rescue medication use, exacerbations, and change in serum fibrinogen concentration after 24 weeks were assessed in exploratory and post hoc analyses, respectively. Measurements and Main Results: Nine hundred seventy-four patients were randomized. After 12 weeks of icenticaftor treatment, no dose-response relationship for change from baseline in trough FEV1 was observed; however, it was observed for E-RS cough and sputum score. A dose-response relationship was observed after 24 weeks for trough FEV1, E-RS cough and sputum and total scores, rescue medication use, and fibrinogen. A dose of 300 mg b.i.d. was consistently the most effective. Improvements for 300 mg b.i.d. versus placebo were also seen in pairwise comparisons of these endpoints. All treatments were well tolerated. Conclusions: The primary endpoint was negative, as icenticaftor did not improve trough FEV1 over 12 weeks. Although the findings must be interpreted with caution, icenticaftor improved trough FEV1; reduced cough, sputum, and rescue medication use; and lowered fibrinogen concentrations at 24 weeks. Clinical trial registered with www.clinicaltrials.gov (NCT04072887).

Improving resident learning on vasectomy: a national survey on urology resident vasectomy training.

INTRODUCTION: Resident training in vasectomy, especially in the office setting on the awake patient, may be limited. The aim of this study is to understand resident exposure to vasectomy and to identify barriers to learning. MATERIALS AND METHODS: An anonymous 18-question survey was distributed to urology residents of the 135 ACGME-accredited urology residencies in the United States. Residents were asked to specify the total number of vasectomies they had performed and in what environment (operating room versus office), their comfort performing vasectomy independently, and any barriers to learning the procedure. RESULTS: In total, 119 residents responded to the survey, representing a 10% response rate. Vasectomy case volumes were variable, with 36.7% of residents logging ≤ 20 vasectomies by their final year of training. Total of 23.4% indicated they did not receive training in perioperative counseling for patients considering vasectomy. Only 64.7% of all residents felt comfortable in the office setting versus 89.1% who felt comfortable in the operating room (p < 0.001). This difference persisted throughout training, and 16.7% of residents in their final year of residency were uncomfortable performing office vasectomy. Total of 60.5% of respondents cited one or more barriers to training, with lack of surgical volume (38.7%), lack of vasectomies in the resident clinic (29.4%), and lack of autonomy when performing the procedure (22.7%) being the most common. CONCLUSIONS: Residents are significantly less comfortable performing vasectomy in the office setting versus in the operating room, including in their graduating year. Residents describe low volume and lack of autonomy as barriers to vasectomy training.

Dose bridging data for mometasone furoate in once-daily fixed-dose inhaled combinations of mometasone furoate/indacaterol and mometasone furoate/ indacaterol/glycopyrronium in patients with asthma.

Once-daily (o.d.) fixed-dose combinations of mometasone furoate/indacaterol acetate (MF/IND) and mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY), both delivered via the Breezhaler® device, are approved for the maintenance treatment of asthma. Across these fixed-dose combinations, while the doses of bronchodilators remain the same, the nominal doses of mometasone furoate in micrograms differ. This article presents the steps followed in bridging the mometasone furoate doses at the corresponding dose strengths in the mometasone furoate formulation delivered via the Twisthaler® and mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulations delivered via the Breezhaler®. These were: (i) bridging the mometasone furoate doses in the Twisthaler® (previously approved) to mometasone furoate doses in the Breezhaler®; (ii) bridging the mometasone furoate doses in the Breezhaler® to mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation. Following this stepwise approach, it was determined that mometasone furoate 80 µg o.d. (medium-dose strength) and 160 µg o.d. (high-dose strength) in mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation provided comparable inhaled corticosteroid efficacy to mometasone furoate 160 µg o.d. (medium-dose strength) and 320 µg o.d. (high-dose strength) in the mometasone furoate/indacaterol acetate formulation, respectively. These doses were used in the PLATINUM Phase III clinical program that investigated the efficacy and safety of mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide combinations in patients with asthma.

Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler® Device in Patients with Asthma.

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Inverse probability of censoring weighting for visual predictive checks of time-to-event models with time-varying covariates.

When constructing models to summarize clinical data to be used for simulations, it is good practice to evaluate the models for their capacity to reproduce the data. This can be done by means of Visual Predictive Checks (VPC), which consist of several reproductions of the original study by simulation from the model under evaluation, calculating estimates of interest for each simulated study and comparing the distribution of those estimates with the estimate from the original study. This procedure is a generic method that is straightforward to apply, in general. Here we consider the application of the method to time-to-event data and consider the special case when a time-varying covariate is not known or cannot be approximated after event time. In this case, simulations cannot be conducted beyond the end of the follow-up time (event or censoring time) in the original study. Thus, the simulations must be censored at the end of the follow-up time. Since this censoring is not random, the standard KM estimates from the simulated studies and the resulting VPC will be biased. We propose to use inverse probability of censoring weighting (IPoC) method to correct the KM estimator for the simulated studies and obtain unbiased VPCs. For analyzing the Cantos study, the IPoC weighting as described here proved valuable and enabled the generation of VPCs to qualify PKPD models for simulations. Here, we use a generated data set, which allows illustration of the different situations and evaluation against the known truth.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

IL-23 mediates murine liver transplantation ischemia-reperfusion injury via IFN-γ/IRF-1 pathway.

Interleukin-23 (IL-23) is a proinflammatory cytokine initially studied in autoimmune disease that has been more recently linked to innate immunity. We observed that the expression of IL-23 is upregulated during hypoxia in a hepatocyte and nonparenchymal cell (NPC) coculture system, as well as during ischemia-reperfusion (I/R) injury in the liver. Interferon regulatory factor-1 (IRF-1) is a transcription factor that induces expression of multiple inflammatory cytokines and has been shown to play a critical role in liver I/R injury. We observed that IL-23 signaling induces not only the IL-17/chemokine (C-X-C motif) ligand 2 (CXCL2) pathway but also the IFN-γ/IRF-1 pathway. Quantification of cytokine genes revealed increased liver expression of IL-17a, CXCL2, and IRF-1 messenger RNA during liver transplantation. Recombinant IL-23 treated hepatocytes, and NPC coculture led to IL-17, CXCL2, IFN-γ, and IRF-1 expression. With anti-IL-17 and anti-Ly6G antibody neutralization, neutrophil recruitment and IFN-γ production were decreased during warm I/R injury. Overexpression of IL-23 in vivo through use of an adenovirus vector also led to expression of IL-17, CXCL2, IFN-γ, and IRF-1. The increased expression of IL-23 also led to increased apoptosis in the liver. By neutralization of IL-23 through use of an anti-IL-23p19 antibody, we were able to attenuate liver damage in a wild-type but not a natural killer T (NKT) cell-deficient mouse. This suggests that IL-23 signaling shares a common pathway with NKT cells. In conclusion, IL-23 is induced early by I/R in the liver. Its signaling leads to activation of the IL-17/CXCL2 and IFN-γ/IRF-1 pathways, resulting in increased apoptosis and necrosis. NEW & NOTEWORTHY IL-23 is expressed early during cold ischemia-reperfusion (I/R), and this expression is associated with expression of IL-17 and chemokine (C-X-C motif) ligand 2. Neutralization of IL-23 during cold I/R can significantly reduce liver damage as well as decrease cytokine production and neutrophil infiltration in the liver. IL-23 appears to activate IFN-γ production in natural killer T cells within the liver which, in turn, activates interferon regulatory factor-1, a known inflammatory transcription factor during I/R injury.

Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease.

BACKGROUND: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear. METHODS: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting ß2 agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (ΔFEV1) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modelling to determine if ΔFEV1 could predict patient outcomes with different treatments. RESULTS: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between ΔFEV1 and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV1 had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled ΔFEV1 values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV1 from baseline with improvements in PROs observed across all treatments when trough FEV1 improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent. CONCLUSIONS: These data suggest that FEV1 improvements post-bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements. TRIAL REGISTRATION: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4.

Population pharmacokinetics of IND/GLY (indacaterol/glycopyrronium) in COPD patients.

OBJECTIVE: Indacaterol/glycopyrronium (IND/GLY) is a fixed-dose combination (FDC) of indacaterol, an inhaled long-acting ß2-agonist (LABA), and glycopyrronium, an inhaled long-acting muscarinic antagonist (LAMA), developed as a maintenance bronchodilator treatment for patients with chronic obstructive pulmonary disease (COPD). A population pharmacokinetic (PK) analysis was performed to describe the PK profiles of indacaterol and glycopyrronium following the twice daily (b.i.d.) and once daily (o.d.) inhalation regimens as FDC or as monotherapies and to determine the effect of covariates. METHODS: PK data in 556 COPD patients were pooled from three phase 3 studies. Two phase 3 studies investigated IND/GLY 27.5/12.5 µg b.i.d. and the third study investigated IND/GLY 110/50 µg o.d. Body weight was included in the model with fixed allometric coefficients for indacaterol and glycopyrronium. RESULTS: Statistically significant effects of smoking, age, and sex on apparent clearance of indacaterol; smoking, and estimated glomerular filtration rate at baseline on apparent clearance and Japanese ethnicity on apparent central volume of distribution of glycopyrronium were identified. CONCLUSION: Systemic exposure to indacaterol and glycopyrronium was shown to be dose-proportional and time-independent following inhalation either as monotherapies or FDC. None of the identified covariate effects was judged to be clinically relevant. There is no PK drug-drug interaction between indacaterol and glycopyrronium in its FDC.

Nitric oxide production upregulates Wnt/ß-catenin signaling by inhibiting Dickkopf-1.

Nitric oxide signaling plays complex roles in carcinogenesis, in part, due to incomplete mechanistic understanding. In this study, we investigated our discovery of an inverse correlation in the expression of the inducible nitric oxide synthase (iNOS) and the Wnt/ß-catenin regulator Dickkopf-1 (DKK1) in human cancer. In human tumors and animal models, induced nitric oxide synthesis increased Wnt/ß-catenin signaling by negatively regulating DKK1 gene expression. Human iNOS (hiNOS) and DKK1 gene expression were inversely correlated in primary human colon and breast cancers, and in intestinal adenomas from Min (Apc(min/+)) mice. Nitric oxide production by various routes was sufficient to decrease constitutive DKK1 expression, increasing Wnt/ß-catenin signaling in colon and breast cancer cells and primary human hepatocytes, thereby activating the transcription of Wnt target genes. This effect could be reversed by RNA interference-mediated silencing of iNOS or treatment with iNOS inhibitors, which restored DKK1 expression and its inhibitory effect on Wnt signaling. Taken together, our results identify a previously unrecognized mechanism through which the nitric oxide pathway promotes cancer by unleashing Wnt/ß-catenin signaling. These findings further the evidence that nitric oxide promotes human cancer and deepens insights in the complex control Wnt/ß-catenin signaling during carcinogenesis.

Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach.

AIMS: Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease. In this study, we used population pharmacokinetic (PK) modelling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and, in turn, to understand the impact of lung bioavailability and residence time on the choice of dosage regimen. METHODS: We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and to characterize amounts of glycopyrronium in systemic compartments and lungs. RESULTS: The model-derived PK parameters were comparable to those obtained with noncompartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments. CONCLUSIONS: The slow absorption from the lungs, together with the rapid elimination from the systemic circulation, could explain how once-daily glycopyrronium provides sustained bronchodilatation with a low incidence of adverse effects in patients with chronic obstructive pulmonary disease. Its extended intrapulmonary residence time also provides pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug.

QSAR--how good is it in practice? Comparison of descriptor sets on an unbiased cross section of corporate data sets.

The quality of QSAR (Quantitative Structure-Activity Relationships) predictions depends on a large number of factors including the descriptor set, the statistical method, and the data sets used. Here we study the quality of QSAR predictions mainly as a function of the data set and descriptor type using partial least squares as the statistical modeling method. The study makes use of the fact that we have access to a large number of data sets and to a variety of different QSAR descriptors. The main conclusions are that the quality of the predictions depends both on the data set and the descriptor used. The quality of the predictions correlates positively with the size of the data set and the range of biological activities. There is no clear dependence of the quality of the predictions on the complexity of the data set. All of the descriptors tested produced useful predictions for some of the data sets. None of the descriptors is best for all data sets; it is therefore necessary to test in each individual case, which descriptor produces the best model. In our tests, 2D fragment based descriptors usually performed better than simpler descriptors based on augmented atom types. Possible reasons for these observations are discussed.

Absolute free energies of binding of peptide analogs to the HIV-1 protease from molecular dynamics simulations.

The constants of binding of five peptide analogs to the active site of the HIV-1 aspartic-protease are calculated based on a novel sampling scheme that is efficient and does not introduce any approximations in addition to the energy function used to describe the system. The results agree with experiments. The squared correlation coefficient of the calculated vs. the measured values is 0.79. The sampling scheme consists of a series of molecular dynamics integrations with biases. The biases are selected based on an estimate of the probability density function of the system in a way to explore the conformational space and to reduce the statistical error in the calculated binding constants. The molecular dynamics integrations are done with a vacuum potential using a short cutoff scheme. To estimate the probability density of the simulated system, the results of the molecular dynamics integrations are combined using an extension of the weighted histogram analysis method (C. Bartels, Chem. Phys. Letters 331 (2000) 446-454). The probability density of the solvated ligand-protein system is obtained by applying a correction for the use of the short cutoffs in the simulations and by taking into account solvation with an electrostatic term and a hydrophobic term. The electrostatic part of the solvation is determined by finite difference Poisson-Boltzmann calculations; the hydrophobic part of the solvation is set proportional to the solvent accessible surface area. Setting the hydrophobic surface tension parameter equal to 8 mol(-1) K(-1) A(-2), absolute binding constants are in the muM to nM range. This is in agreement with experiments. The standard errors determined from eight repeated binding constant determinations are a factor of 14 to 411. A single determination of a binding constant is done with 499700 steps of molecular dynamics integration and 4500 finite difference Poisson-Boltzmann calculations. The simulations can be analyzed with respect to conformational changes of the active site of the HIV-1 protease or the ligands upon binding and provide information that complements experiments and can be used in the drug development process.

Enhancement of drug delivery in tumors by using interaction of nanoparticles with ultrasound radiation.

Efficacy and safety of cancer chemo- and biotherapy are limited by poor penetration of anti-cancer drugs from blood into tumor cells. Tumor blood vessel wall, slow diffusion in the interstitium, and cancer cell membrane create physiological barriers for anti-cancer drugs, in particular promising macromolecular agents. Recently, we proposed to use selective accumulation of exogenous nano- and microparticles in tumors followed by ultrasound-induced cavitation for safe and efficient drug and gene delivery. In this paper, we first investigated the influence of polystyrene nanoparticles (100 and 280 nm in diameter and concentration up to 0.2% w/w) on cavitation threshold in water at the frequency of 20 kHz. Then, using optimal irradiation parameters found in the first part of this work, we studied efficacy of cancer chemotherapy with this technique. The experiments were performed in athymic nude mice bearing human colon KM20 tumors, which are highly resistant to chemotherapy. Ultrasound with the frequency of 20 kHz in combination with i.v. injected polystyrene nanoparticles was applied to enhance delivery of chemotherapeutic agent 5-fluorouracil. Our studies demonstrated that ultrasound irradiation in combination with the nanoparticle and drug injections significantly decreased tumor volume and resulted in complete tumor regression at optimal irradiation conditions, while the volume of control (non-irradiated) tumors increased despite drug injections. These data suggest that ultrasound-induced drug delivery may improve efficacy of current cancer treatment regimens.

Effective atom volumes for implicit solvent models: comparison between Voronoi volumes and minimum fluctuation volumes.

An essential element of implicit solvent models, such as the generalized Born method, is a knowledge of the volume associated with the individual atoms of the solute. Two approaches for determining atomic volumes for the generalized Born model are described; one is based on Voronoi polyhedra and the other, on minimizing the fluctuations in the overall volume of the solute. Volumes to be used with various parameter sets for protein and nucleic acids in the CHARMM force field are determined from a large set of known structures. The volumes resulting from the two different approaches are compared with respect to various parameters, including the size and solvent accessibility of the structures from which they are determined. The question of whether to include hydrogens in the atomic representation of the solute volume is examined. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1857-1879, 2001