Mechanism Of Action
UTIBRON NEOHALER contains both indacaterol and glycopyrrolate. The mechanisms of action described below for the individual components apply to UTIBRON NEOHALER. These drugs represent 2 different classes of medications (a LABA and an anticholinergic) that have different and additive effects on clinical and physiological indices.
Indacaterol is a long-acting beta2-adrenergic agonist (LABA). When inhaled, indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of these receptors is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. The clinical significance of these findings is unknown.
Glycopyrrolate is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced broncho-constrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.
The QTc interval was studied in TQT studies with UTIBRON NEOHALER and with each of the monotherapy components. The TQT studies with indacaterol and glycopyrrolate demonstrated that neither of the compounds had a relevant effect on the corrected QT interval at supratherapeutic and therapeutic doses (for glycopyrrolate only a supratherapeutic dose was tested).
In a randomized, partially-blinded, placebo-and positive-controlled, crossover TQT study in 84 healthy subjects a supratherapeutic dose of UTIBRON NEOHALER (indacaterol/glycopyrrolate 440/499.2 mcg) was administered. This is a 16/32 dose multiple compared to a single dose of the recommended 27.5/15.6 mcg twice-daily dosage of UTIBRON NEOHALER which resulted in exposure multiples for mean Cmax of 9.3 for indacaterol and 35.2 for glycopyrrolate compared to steady-state pharmacokinetics of UTIBRON NEOHALER 27.5/15.6 mcg twice-daily. The mean maximal change from baseline in QTcI compared to placebo was 8.70 msec (2-sided 90% CI 7.3, 10.1) at 30 minutes after dosing. Although a marginal QT effect of UTIBRON NEOHALER was observed at the supratherapeutic dose, it is unlikely there will be a clinically relevant effect at the therapeutic exposure.
Following inhalation of UTIBRON NEOHALER, the median time to reach peak plasma concentrations of indacaterol and glycopyrrolate was achieved rapidly at approximately 15 minutes and 5 minutes, respectively.
The steady-state systemic exposure (AUC0-12h,ss; CRmax,ssR) to indacaterol and glycopyrrolate is similar after the twice-daily inhalation of 2 (times 2) capsules of UTIBRON NEOHALER 27.5 mcg/15.6 mcg as compared to the twice-daily inhalation of the monotherapy products indacaterol 27.5 mcg (times 2) alone or glycopyrrolate 15.6 mcg (times 2) alone respectively.
Absolute bioavailability of indacaterol after an inhalation dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and intestine absorption. Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-hour dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.
Following repeated once-daily inhalation in patients with COPD, pharmacokinetic steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time. With once-daily doses of 124.8 mcg and 249.6 mcg, steady-state exposure to glycopyrrolate (AUC over the dosing interval) was about 1.4-to 1.7-fold higher than after the first dose.
After intravenous infusion, the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 L, indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1% to 95.3% and 95.1% to 96.2%, respectively.
After intravenous administration, the steady-state volume of distribution (Vss) of glycopyrrolate was 83 L and the volume of distribution in the terminal phase (Vz) was 376 L. The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.
In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.
After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one-third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C-and N-dealkylated products were further metabolites identified.
In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono-and bishydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate. Glucuronide and/or sulfate conjugates of glycopyrrolate were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.
In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/h and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2% to 6% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with greater than or equal to 90% of the dose recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 56 hours, which is consistent with the observed time to steady-state of approximately 12 to 15 days.
Renal elimination of parent drug accounts for about 60% to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30% to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.
Following inhalation of single and repeated once-daily doses between 62.4 mcg and 249.6 mcg glycopyrrolate by healthy volunteers and patients with COPD, mean renal clearance of glycopyrrolate was in the range of 17.4 L/h and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrrolate.
Glycopyrrolate plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life of glycopyrrolate was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.
There is no pharmacokinetic drug-drug interaction resulting from the concomitant administration of inhaled
glycopyrrolate and inhaled indacaterol based on steady-state exposure data.
No specific drug-drug interaction studies were conducted with UTIBRON NEOHALER. Information on the potential for interactions for UTIBRON NEOHALER is based on the potential for each of its 2 monotherapy components.
Effect Of Co-Administered Drugs On Indacaterol And Glycopyrrolate Exposure
Inhibitors of Cytochrome P450 3A4 and P-gp Efflux Transporter
Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir). Coadministration of indacaterol 300 mcg (single dose) with verapamil (80 mg 3 times a day for 4 days) showed 2-fold increase in indacaterol AUC0-24h, and 1.5-fold increase in indacaterol Cmax. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg 4 times a day for 7 days) showed a 1.4-fold increase in indacaterol AUCR024hR, and 1.2-fold increase in indacaterol Cmax. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg twice-daily for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24h, and 1.3-fold increase in indacaterol Cmax. Coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice-daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC0-24h whereas indacaterol Cmax was unaffected [see DRUG INTERACTIONS].
Cimetidine or Other Inhibitors of Organic Cationic Transport
In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport that is thought to contribute to the renal excretion of glycopyrrolate, increased total exposure (AUC) to glycopyrrolate by 22% and decreased renal clearance by 23%.
Effect of UTIBRON on co-administered drugs exposure
In vitro studies show that UTIBRON NEOHALER is not likely to inhibit or induce the metabolism of other drugs, nor processes involving drug transporters.
In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.
In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 85 years), body weight (45 to 120 kg), gender, smoking status, and baseline FEV1 on systemic exposure of either indacaterol or glycopyrrolate following inhalation of UTIBRON NEOHALER.
Similarly no relevant covariate effect (of age, body weight, gender, smoking status, and baseline FEV1) was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.
Patients With Renal Impairment
Due to the very low contribution of the urinary pathway to total body elimination of indacaterol, a study in renally impaired subjects was not performed.
Renal impairment has an impact on the systemic exposure to glycopyrrolate. A moderate mean increase in total systemic exposure (AUC last) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment [estimated GFR greater than or equal to 30 mL/min/1.73m2] and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease [estimated GFR less than 30 mL/min/1.73m2] [see Use In Specific Populations].
Patients With Hepatic Impairment
Based on the clinical pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild and moderate hepatic impairment. UTIBRON NEOHALER has not been evaluated in subjects with severe hepatic impairment.
Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed [see Use In Specific Populations].
Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrrolate is cleared predominantly from the systemic circulation by renal excretion.
There was no evidence of a clinically significant ethnic/race effect (across Caucasian, Chinese, and Japanese subjects) on the systemic exposure to indacaterol and glycopyrrolate following inhalation of UTIBRON NEOHALER.
Similarly, no relevant ethnic effect was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.
The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.
The effects of pharmacogenomic variants on the pharmacokinetics of glycopyrrolate have not been investigated.
Eye findings were seen for glycopyrrolate and were observed in Wistar rats at inhaled doses of 0.67 mg/kg/day and higher (approximately 280 times the MRHD in adults on an AUC basis) based upon findings of anterior capsule opacity, prominent anterior suture line, and anterior cataract. No eye findings in Wistar rats were observed at an inhaled dose of 0.09 mg/kg/day (approximately 60 times the MRHD in adults on an AUC basis). Eye findings were observed in beagle dogs at an inhaled dose of 0.33 mg/kg/day (approximately 150 times the MRHD in adults on an AUC basis) based upon findings of conjunctival hyperemia and corneal opacity. No eye findings in beagle dogs were observed at an inhaled dose of 0.12 mg/kg/day (approximately 100 times the MRHD in adults on an AUC basis).
The safety and efficacy of UTIBRON NEOHALER were evaluated in a clinical development program that included 3 dose-ranging trials, 2 lung function trials of 12 weeks duration (placebo-controlled and active-controlled) and a 12-month long-term safety trial. The efficacy of UTIBRON NEOHALER is based primarily on the dose-ranging trials in 562 subjects with COPD or asthma and the 2 placebo-and active-controlled confirmatory trials in 2043 subjects with additional support from one active-controlled 12-month trial in 615 subjects with COPD.
Dose selection for UTIBRON NEOHALER for COPD was based on data for the individual components, indacaterol and glycopyrrolate.
Indacaterol dose selection in UTIBRON NEOHALER is based on the registered dose of 75 mcg once-daily and is also supported by a single-dose, multicenter, randomized, double-blind, placebo-controlled, crossover study in asthma evaluating 5 doses of indacaterol in 91 subjects, (37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily (QD), and
27.5 mcg twice-daily (BID)). A dose-related increase in FEV1 AUC0-24h compared with placebo was observed. The differences in change from baseline in FEV1 AUCR0-24h Rafter single dosing for the indacaterol 37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily and the 27.5 mcg twice-daily doses compared to placebo were 0.099 L (95% CI: 0.069, 0.128),
0.132 L (0.103, 0.162), 0.143 L (0.114, 0.171), 0.187 L (0.157, 0.216), and 0.121 L (0.092, 0.151), respectively. These results supported the evaluation of indacaterol 27.5 mcg twice-daily in the confirmatory COPD trials. UTIBRON NEOHALER is not indicated for asthma.
Figure 1. Adjusted mean change from baseline in FEV1(L) over 24 hours on Day 1
Dose selection for glycopyrrolate in UTIBRON NEOHALER in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate (15.6 mcg,
31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily) or placebo in 388 subjects with COPD. The differences in trough FEV1 from baseline after 28 days compared to placebo for the 15.6 mcg,
31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and for 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily doses were 0.083 L (95% CI: 0.030, 0.136), 0.098 L (0.048, 0.148), 0.090 L (0.038, 0.142), 0.176 L (0.132, 0.220), 0.139 L (0.089, 0.189),
0.167 L (0.115, 0.219), and 0.177 L (0.132, 0.222), respectively. The dose-ranging results supported the evaluation of glycopyrrolate 15.6 mcg twice-daily in the confirmatory COPD trials.
Figure 2. Adjusted mean change from baseline in FEV1 (L) over 24 hours on Days 1 and 28
Based on the findings from dose-ranging studies of the individual components, a twice-daily dose of indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg was evaluated in the confirmatory COPD trials.
The clinical development program for UTIBRON NEOHALER included two (Trial 1 and Trial 2) 12-week, randomized, double-blinded, placebo-and active-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy and safety of UTIBRON NEOHALER; and one 12-month, randomized, double-blind, active-controlled trial (Trial 3) that evaluated bronchodilation and effects on long-term safety.
The 12-week trials evaluated the efficacy of 2038 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a post-albuterol FEV1 greater than or equal to 30% and less than 80% of predicted normal values, had a ratio of FEV1/FVC of less than 0.7, and were symptomatic as determined by a Modified Medical Research Council (mMRC) score greater than or equal to 2. Of the 2038 subjects included in the efficacy analysis, 63% were male and 91% were Caucasian. They had a mean age of 63 years and an average smoking history of 47 pack-years, with 52% identified as current smokers, and 46% used concomitant inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV1 was 55% (range: 29% to 79%), the mean postbronchodilator FEV1/FVC ratio was 50% (range: 19% to 71%), and the mean percent reversibility was 23% (range: 0% to 144%).
Trial 1 and Trial 2 evaluated UTIBRON NEOHALER (indacaterol/glycopyrrolate) 27.5 mcg/15.6 mcg twice-daily (BID), indacaterol 27.5 mcg BID, glycopyrrolate 15.6 mcg BID, and placebo BID. The primary endpoint was the change from baseline in FEV1 AUCR0-12h Rfollowing the morning dose at Day 85 (defined as the mean FEV1 change from baseline over 0 to 12 hours divided by 12 hours) compared with placebo, glycopyrrolate 15.6 mcg BID, and indacaterol 27.5 mcg BID. The comparison of UTIBRON NEOHALER with indacaterol 27.5 mcg and glycopyrrolate 15.6 mcg was assessed to evaluate the contribution of the individual comparators to UTIBRON NEOHALER. In both trials, UTIBRON NEOHALER demonstrated a larger increase in mean change from baseline in FEV1 AUCR0-12h Rcompared to placebo, indacaterol 27.5 mcg BID, and glycopyrrolate 15.6 mcg BID (see Table 2).
Table 2. Least squares (LS) mean change from baseline in FEV1 (L) AUCR(0-12hRR)R at Day 85 in Trials 1 and 2 (Intentto-Treat Population)
||FEV1 (L) AUCR0-12h at Week 12 Difference from
27.5 mcg BID*
15.6 mcg BID*
|Trial 1 (N=996)
27.5 mcg/15.6 mcg BID
|Trial 2 (N=1039)
27.5 mcg/15.6 mcg BID
|N = Number in intent-to-treat population
* The indacaterol and glycopyrrolate comparators used the same inhaler and excipients as UTIBRON NEOHALER
With the limited data available, there was no suggestion of a difference in FEV1 AUCR0-12h Rwith respect to age, sex, degree of airflow limitation, GOLD stage, smoking status, or inhaled corticosteroid use.
In Trial 1 and Trial 2, serial spirometric evaluations throughout the 12-hour dosing interval were performed in all subjects at Days 1 and 85. The spirometric curves from Trial 1 at Days 1 and 85 are displayed in Figure 3. In Trial 2, the results for UTIBRON NEOHALER in FEV1 AUCR0-12hR were similar to those observed in Trial 1.
Figure 3. Adjusted mean change from baseline in FEV1 (L) over 12 hours on Days 1 and 85 in Trial 1 (All patient Population)
The peak FEV1 was defined as the maximum FEV1 recorded within 4 hours after the morning dose on Days 1 and 85. The mean peak FEV1 improvement from baseline for UTIBRON NEOHALER compared with placebo at Day 1 and at Day 85 was 0.185 L and 0.290 L (Trial 1) and 0.151 L and 0.260 L (Trial 2), respectively. The median time to onset on Day 1, defined as a 100 mL increase from baseline in FEV1, was 12 minutes and 16 minutes in Trials 1 and 2, respectively, in subjects receiving UTIBRON NEOHALER.
In Trials 1 and 2, patients treated with UTIBRON NEOHALER used less daily rescue albuterol compared to patients treated with placebo.
The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 2, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) was 57%, 46%, 48%, and 39%, for UTIBRON NEOHALER, glycopyrrolate, indacaterol, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1, 2.3), 1.5 (95% CI 1.1, 2.2), and 2.2 (95% CI 1.5, 3.2), for UTIBRON NEOHALER vs. glycopyrrolate, UTIBRON NEOHALER vs. indacaterol, and UTIBRON NEOHALER vs. placebo, respectively. In Trial 1, the trends were similar, with odds ratios of 1.4 (95% CI 1.0, 2.0), 1.1 (95% CI 0.8, 1.7), and 2.9 (95% CI 1.9, 4.2), for UTIBRON NEOHALER vs. glycopyrrolate, UTIBRON NEOHALER vs. indacaterol, and UTIBRON NEOHALER vs placebo, respectively.
52-week Effects on Lung Function
At week 52 (Trial 3), UTIBRON NEOHALER demonstrated a significant treatment effect with an increase of 0.080 L in pre-dose trough FEV1 compared to indacaterol 75 mcg once-daily.