Effect of indacaterol on dynamic lung hyperinflation and breathlessness in patients with COPD

Abstract Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak- and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40–80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) 120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak- and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 [95% CI: 118–517]; p=0.0033) and isotime IC (268 mL [95% CI: 104–432]; p=0.0026). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, FEV1, dyspnoea (BDI/TDI and Borg CR10 scale) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses

Background Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. Objective This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. Methods Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. Results QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. Conclusion QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma

Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-hour bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥40 years; smoking history of ≥10 pack-years) were randomized to receive NVA237 50 µg once daily followed by placebo or placebo followed by NVA237 50 µg for 14 days. Treatment periods were separated by a 7–14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV1) derived from the area under the curve (AUC) between 0 and 24 hour post-dose on Day 14. The 24-h FEV1 profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV1 AUC0–24 h values between NVA237 and placebo was 163 mL (p<0.001). There were significant increases in mean FEV1 AUC0–12 h (LS mean difference 165 mL, p=0.001) and FEV1 AUC12–24 h (161 mL, p<0.001) versus placebo. NVA237 significantly improved peak FEV1 (by 208 mL, p<0.001) and trough FEV1 (by 154 mL, p=0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-hour bronchodilation in patients with COP

Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three-period, cross-over, placebo- and positive-controlled study

Objective Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. Methods This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supratherapeutic dose (8-fold clinical dose in COPD patients) of 400 μg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazett-corrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. Results A total of 73 healthy male (N = 35) and female (N = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 min, with the upper limit of the two-sided 90% CI being 4.80 ms, excluding a relevant QT-effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of –2.88 (90% CI: –3.78, –1.99) beats per min (bpm) over whole time range and a maximum of –5.87 (90% CI: –7.82, –3.92) bpm at 5 h post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median Tmax = 7 min). All the treatments were well tolerated with no serious adverse events. Conclusion A supratherapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval

Effect of cimetidine, a model drug for inhibition of the organic cation transport in the kidney, on the pharmacokinetics of glycopyrronium

Objective: Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. Methods: In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 µg glycopyrronium was inhaled alone and on day 4 of a 6 day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast) and renal clearance (CLr) of glycopyrronium. Results: Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12-1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70-0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths and severe adverse events. Conclusion: Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport

The pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD)

Objective: NVA237 (glycopyrronium bromide) is a once-daily long-acting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild to moderate COPD patients. Methods: In this double-blind, parallel-group study, COPD patients were randomised to a 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14. Results: The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min post-inhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 to 200 µg dose range. The average exposure was 1.4- to 1.7-fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t½) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within one week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 L/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate. Conclusions: The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalatio

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug-drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first-pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady-state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27-fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically-based pharmacokinetic (PBPK) model, which well-described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug-drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration-time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks

Novel Bruton’s tyrosine kinase inhibitor remibrutinib: Assessment of drug-drug interaction potential as a perpetrator of cytochrome P450 enzymes and drug transporters and the impact of covalent binding on possible drug interactions

Purpose Pharmacokinetic drug–drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present results of in vitro studies and a clinical study to assess the DDI potential of Bruton’s Tyrosine kinase inhibitor, remibrutinib as an inhibitor of drug-metabolising enzymes and drug transporters, and as an inducer. The pharmacokinetics of oral hormonal contraceptives (OC) in combination with remibrutinib were also evaluated. Remibrutinib is a covalent inhibitor of BTK and carries a reactive acrylamide moiety (warhead), so the potential contribution of covalent binding to observed interactions was investigated. Methods DDI assessment was based on initial in vitro studies, a clinical DDI study and an endogenous biomarker assessment. Beyond the potential effect on OC, the prediction of concomitant medications with remibrutinib and Cytochrome P450 (CYP) metabolism was evaluated. The impact of covalent binding was assessed by synthesising an identical reference molecule but with an inactivated warhead. Results Overall, the study revealed minor DDIs with limited clinical relevance for remibrutinib with CYP enzymes and drug transporters. Interestingly, the reactive warhead of remibrutinib had no impact on CYP enzyme and transporter inhibition, including time-dependent inhibition of CYP3A4, but may increase the induction potential of remibrutinib. Observed inhibition of metabolic enzymes indicated that remibrutinib is a weak inhibitor of CYP3A4 and CYP2C9 and is not a clinically relevant inhibitor of uptake and efflux transporters, with the exception of intestinal P-glycoprotein and breast cancer resistance protein inhibition. . Conclusion Oral contraceptives may be safely administered and are effective when given with pharmacologically relevant doses of remibrutinib

Validation of computational fluid dynamics in CT-based airway models with SPECT/CT

Advances in Knowledge This article demonstrates how to use novel functional imaging methods using a combination of CT and patient specific computer simulations to accurate describe the respiratory function and increase the knowledge of asthma phenotypes. Outcome is compared and validated using SPECT CT scans. Future uses of this novel approach in clinical practice are discussed. Implication for patient care These methods allow for a highly detailed analysis of the respiratory system with a minimal patient involvement. Therapies and treatments could be optimized in a personalised fashion to maximize the patient’s benefit and reduce the cost by eliminating inefficient therapies. Summary statement This paper presents an important step in bringing high level computer simulations closer to the clinical practice by demonstrating their validity through comparison with state-of-the-art imaging modalities. It demonstrates that imaging modalities contain a large amount of information that can be used as a boundary condition for patient specific simulation making these models accurate and personalized