Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients

David Miller, Soniya Vaidya, Juergen Jauernig, Brian Ethell, Kristina Wagner, Rajkumar Radhakrishnan, Hanns-Christian Tillmann, David Miller, Soniya Vaidya, Juergen Jauernig, Brian Ethell, Kristina Wagner, Rajkumar Radhakrishnan, Hanns-Christian Tillmann

Abstract

Background: Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo.

Methods: This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study.

Results: Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%).

Conclusions: In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated.

Trial registration: ClinicalTrials.gov NCT03257995 June 06, 2017.

Keywords: Asthma; Efficacy; LABA; Pharmacodynamics; Pharmacokinetic; Randomised control trial.

Conflict of interest statement

*Soniya Vaidya was an employee of Novartis Institutes for BioMedical Research, Inc., Cambridge, MA during the conduct of the study.

The authors received no compensation related to the development of the manuscript. Hanns-Christian (HCT) is an employee of and holds shares of Novartis Pharma AG. Brian Ethell (BE) is an employee of and holds shares of Novartis Pharma AG. Juergen Jauernig (JJ) is an employee and shareholder of Novartis Pharma AG. Dr. Soniya Vaidya (SV) is an employee of Axcella Health, Inc. and shareholder of Novartis Pharma AG.

Dr. S. David Miller does not report any conflict of interest (DV). The authors reported no conflict of interest relevant to the work presented here.

Figures

Fig. 1
Fig. 1
Study design. *o.d, once daily
Fig. 2
Fig. 2
Significant improvement in trough FEV1 (mL) with indacaterol maleate and indacaterol acetate versus placebo at Day 14. Data presented as LS mean treatment differences (95% CI). CI, confidence interval; FEV1, forced expiratory volume in 1 s; LS, least square; N, number of patients
Fig. 3
Fig. 3
Improvement in FEV1 AUC0-4h (mL) with indacaterol maleate and indacaterol acetate versus placebo at Day 14. Data presented as LS mean treatment differences (95% CI). AUC, area under the curve; CI, confidence interval; FEV1, forced expiratory volume in 1 s; LS, least square; N, number of patients
Fig. 4
Fig. 4
Improvement in PEF (L/min) with indacaterol maleate and indacaterol acetate versus placebo at Day 14. Data are presented as LS mean treatment difference (95% CI). LS, least square; N, No. of patients; PEF, peak expiratory flow
Fig. 5
Fig. 5
Plasma concentration–time profiles for indacaterol maleate and indacaterol acetate on Day 14. Data presented as arithmetic mean ± SD; error bars indicate SD values; o.d., once daily

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