An Evaluation of the Pharmacokinetics, Safety, and Tolerability of Aclidinium/Formoterol Fixed-Dose Combination Administered in Chinese Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction associated with chronic inflammation in the airways and lungs due to noxious particles or gases [1]. COPD is a leading cause of mortality worldwide and poses a significant global health burden [2]. In China, the prevalence of COPD is estimated to be as high as 8.2% in people aged over 40 years [3].

Long-acting muscarinic antagonists (LAMAs) have been shown to provide clinical benefits in the treatment of COPD by blocking muscarinic acetylcholine receptors in the bronchial smooth muscle, thereby decreasing cholinergic tone and relaxing the airways [1, 4]. In addition, long-acting β₂-agonists (LABAs) stimulate the bronchial smooth muscle, resulting in increased airway caliber [1]. This reduction in bronchoconstriction improves airflow, reduces breathlessness and COPD exacerbations, increases exercise tolerance, and improves quality of life [1, 5].

Clinical studies have shown that combination treatment with a LABA and a LAMA results in greater improvement in bronchodilation, as well as better symptom control, compared with monotherapies [1, 4, 6]. Consequently, several combinations of LABAs and LAMAs are approved for the treatment of COPD, including indacaterol/glycopyrronium [7, 8], vilanterol/umeclidinium [9], tiotropium/olodaterol [10, 11], glycopyrrolate/formoterol [12, 13], and aclidinium/formoterol [14, 15]. Of these, indacaterol/glycopyrronium [16], vilanterol/umeclidinium [17] and glycopyrrolate/formoterol [18] have been approved in China.

The major metabolic pathways for aclidinium in humans are non-enzymatic and enzymatic hydrolysis of its carboxylic ester moiety, which produces two inactive metabolites, LAS34823 and LAS34850. Although the genetic locus of the enzyme responsible for the hydrolysis of aclidinium (butyrylcholinesterase) contains polymorphisms [19, 20], variation in pharmacokinetic (PK) variables for other LAMAs was low between different ethnicities in two studies [21, 22]; therefore, ethnicity was not expected to influence the PK of aclidinium/formoterol. This study aimed to bridge the known PK, safety, and tolerability characteristics of aclidinium bromide/formoterol fumarate 400/12 μg twice daily in patients from China with moderate-to-severe COPD.

This study characterized the PK, safety, and tolerability of aclidinium/formoterol 400/12 µg twice daily in patients from China with moderate-to-severe COPD. When compared with previous studies, the demographic and baseline characteristics of the study population were found to be representative of the intended COPD patient population [23]. Moreover, aclidinium/formoterol was well-tolerated, and safety outcomes were similar to the known safety profile of aclidinium and formoterol in other populations [24‐26].

While it is important to note that differences in PK between healthy volunteers and patients with COPD may be due to the disease itself, a number of previous studies have examined the single- and multiple-dose PK of aclidinium/formoterol in both healthy volunteers [27] and those with COPD [28]. In a phase IIa, multiple-dose study of 24 patients in the US with moderate-to-severe COPD who received aclidinium/formoterol 400/12 μg, day 1 C_max and area under the plasma concentration–time curve (AUC_0−t) for aclidinium were more than double the levels found in this analysis (102.0 pg/mL and 228.30 h·pg/mL, respectively), with a similar T_max of 5 min post-dose [28]. This difference was maintained at 5 days, where C_max,ss was 128.4 pg/mL and AUC_0−t steady state was 404.3 h·pg/mL. A similar pattern was found with formoterol, where day 1 C_max and AUC_0−t were approximately doubled (9.6 pg/mL and 42.3 h·pg/mL, respectively), and day 5 C_max was more than doubled (16.7 pg/mL), compared with this study. Despite these differences, the aclidinium R_ac (1.38) was similar to this study (formoterol value was not disclosed). In a phase I, single-dose study of 30 healthy volunteers in Germany who received aclidinium/formoterol 400/12 μg, aclidinium C_max was six times greater (270 pg/mL) and AUC_0−t was three times higher (229 h·pg/mL) than the values observed in this study, although T_max was comparable (0.08 h) [27]. In addition, formoterol PK values were approximately double the values in this study (C_max 9.3 pg/mL; AUC_0−t 32.4 h·pg/mL), with a comparable T_max of 0.08 h.

A number of PK studies examining aclidinium 400 μg monotherapy, which has comparable PK as the combination product, have also been conducted [29, 30]. In a phase I, multiple-dose study of 30 healthy US volunteers receiving aclidinium 400 μg, C_max and AUC_0−t were both approximately four times greater than in this study at day 1 (194.2 pg/mL and 324.9 h·pg/mL, respectively), with an increase of four times and three times, respectively, on the evening of day 7 compared with day 5 in this study (C_max 240.5 pg/mL and AUC_0−t 468.4 h·pg/mL) [29]; however, T_max remained similar (0.08 h). A phase I, open-label, multiple-dose PK study of 24 patients from Germany with COPD segregated patients by age group (younger patients, mean age 53 years; older patients, mean age 73 years; both n = 12) [30]. Patients receiving aclidinium 400 μg had a C_max of 82.3 and 71.2 pg/mL, with an AUC_τ of 193.5 h·pg/mL and 171.3 h·pg/mL on day 1 for younger and older patients, respectively, approximately double the values found in this study. These levels were maintained at day 3 (C_max 86.1 and 67.8 pg/mL, and AUC_τ 199.6 and 191.1 h·pg/mL). T_max occurred slightly later than in this study, at 0.17 and 0.25 h for younger and older patients, respectively, at day 1, and 0.25 h for both patient age groups at day 3.

In comparing these data, it would appear that C_max and AUC_τ values were lower in Chinese patients when compared with the largely Caucasian patient populations of the US and German studies. However, T_max values were generally similar, except for German patients in the de la Motte study, who had a longer T_max in both younger and older patient groups [28, 30]. The lower exposures noted in Chinese patients are likely related to the suboptimal inhalation technique in this study, as discussed in the limitations.

Limitations of this study include the low patient numbers; however, the number of patients included is typical of a bridging study. The PK of inhaled products, either from a DPI or a metered-dose inhaler, is largely dependent on a proper inhalation technique. Drugs such as aclidinium have very poor oral availability, while formoterol has modest oral availability; therefore, the majority of systemic exposure comes from drugs deposited in the lung [14, 15, 31, 32]. Thus, the high between-patient variability observed in some patients is likely due to a suboptimal inhalation technique, particularly for formoterol on day 1; numerous patients did not have the expected early peak in T_max indicative of lung absorption, but rather had a median T_max at approximately 1 h post-treatment, suggesting primarily gastrointestinal absorption [14, 15]. Furthermore, although the day 5 formoterol profiles showed consistently earlier T_max at 5 min (indicative of lung absorption), reflecting a better inhalation technique, many patients also had secondary peaks in T_max at approximately 2 h, indicative of gastrointestinal absorption [14, 15]. In addition, several patients had almost flat profiles for both aclidinium and formoterol, indicating a lack of complete dose delivery. Several other potential causes of between-patient variability have been reported and should also be given consideration.

In summary, aclidinium/formoterol 400/12 µg was well-tolerated in patients from China with moderate-to-severe COPD, and safety findings were consistent with the known safety profile of aclidinium and formoterol. However, a suboptimal inhalation technique among some patients likely influenced absorption of aclidinium/formoterol, leading to lower exposure and contributing to the high between-patient variability in PK characteristics.