BEVESPI AEROSPHERE Pressurised inhalation, suspension Ref.[51295] Active ingredients: Eformoterol Formoterol and Glycopyrronium bromide Glycopyrronium

Following inhalation of the glycopyrronium and formoterol combination, the pharmacokinetics of each component was similar to those observed when each active substance was administered separately. For pharmacokinetic purposes, each component can therefore be considered separately.

Effect of a spacer

The use of Bevespi Aerosphere with the Aerochamber Plus Flow-Vu spacer in COPD patients increased the total systemic exposure to glycopyrronium (as measured by AUC_0-12) by 16% while formoterol exposure was unchanged.

Absorption

Following inhaled administration of Bevespi Aerosphere in subjects with COPD, glycopyrronium C_max occurred at approximately 5 minutes, and formoterol C_max occurred within 20 to 60 minutes. Steady state is achieved within 2-3 days of repeated dosing of Bevespi Aerosphere, and the extent of exposure is approximately 2.3 times and 1.5 times higher than after the first dose, for glycopyrronium and formoterol, respectively.

A lung deposition study with Bevespi Aerosphere conducted in healthy volunteers demonstrated that on average 38% of the nominal dose is deposited into the lung. Both central and peripheral deposition were observed.

Distribution

Glycopyrronium

The estimated glycopyrronium Vc/F (volume of the central compartment), and Vp1/F (volume of the peripheral compartment) are 741 L, and 2 990 L, respectively, via population pharmacokinetic analysis. Over the concentration range of 2-500 nmol/L, plasma protein binding of glycopyrronium ranged from 43% to 54%.

Formoterol

The estimated formoterol Vc/F (volume of the central compartment), and Vp1/F (volume of the peripheral compartment) are 1 030 L, and 647 L, respectively, via population pharmacokinetic analysis. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%.

Biotransformation

Glycopyrronium

Based on literature, and an in-vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

In-vitro studies indicate the glycopyrronium does not inhibit any subtype of cytochrome P450 and that there is no induction of CYP1A2, 2B6, or 3A4.

Formoterol

The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for Odemethylation.

In-vitro studies indicate that formoterol does not inhibit the CYP450 enzymes at therapeutically relevant concentrations.

Elimination

After intravenous administration of a 0.2 mg dose of radiolabelled glycopyrronium, 85% of the dose was recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile. The terminal elimination half-life of glycopyrronium following oral inhalation derived via population pharmacokinetics analysis was 15 hours.

The excretion of formoterol was studied in six healthy subjects following simultaneous administration of radiolabelled formoterol via the oral and intravenous routes. In that study, 62% of the radiolabelled formoterol was excreted in the urine while 24% was eliminated in the faeces. The terminal elimination half-life of formoterol following oral inhalation derived via population pharmacokinetics analysis was 13 hours.

Linearity/non-linearity

Linear pharmacokinetics were observed for glycopyrronium (dose range: 14.4 to 115.2 mcg) and formoterol (dose range: 2.4 to 19.2 mcg) after oral inhalation.

Special populations

Elderly

Based on available data, no adjustment of the dose of Bevespi Aerosphere in geriatric patients is necessary.

Renal impairment

Studies evaluating the effect of renal impairment on the pharmacokinetics of glycopyrronium and formoterol have not been conducted. The effect of renal impairment on the exposure to glycopyrronium and formoterol for up to 12 weeks was evaluated in a population pharmacokinetic analysis. Estimated glomerular filtration rate (eGFR) varied from 30-196 mL/min, representing a range of moderate to no renal impairment. The systemic exposure (AUC_0-12) in subjects with COPD with moderate-severe renal impairment (eGFR of 30-45 mL/min) is approximately 30% higher for glycopyrronium compared to subjects with COPD with normal renal function (eGFR of >90 mL/min). Subjects with COPD with both low body weight and moderate-severe impaired renal function may have an approximate doubling of systemic exposure to glycopyrronium. Renal function was found not to affect exposure to formoterol.

Hepatic impairment

No pharmacokinetic studies have been performed with Bevespi Aerosphere in patients with hepatic impairment. However, because formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment. Glycopyrronium is primarily cleared from the systemic circulation by renal excretion and hepatic impairment would therefore not be expected to lead to unsafe systemic exposure.

Other special populations

A population pharmacokinetic analysis of glycopyrronium was performed based on data collected in a total of 311 subjects with COPD. The pharmacokinetics of glycopyrronium was best described by a two-compartment disposition model with first-order absorption and linear elimination. The typical clearance (CL/F) of glycopyrronium was 124 L/h.

A population pharmacokinetic analysis of formoterol was performed based on data collected in a total of 437 subjects with COPD. The pharmacokinetics of formoterol was best described by a twocompartment disposition model with a first-order rate constant of absorption and linear elimination. The typical clearance (CL/F) of formoterol was 99 L/h.

Dose adjustments are not necessary based on the effect of age, sex and weight on the pharmacokinetic parameters of glycopyrronium and formoterol.

There were no major differences in total systemic exposure (AUC) for both compounds between healthy Japanese and Western subjects. Insufficient pharmacokinetic data are available to compare exposure for other ethnicities or races.

Non-clinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

The toxicity observed in studies with the combination of glycopyrronium and formoterol in dogs were associated with the pharmacological actions of formoterol, including effects mainly on the cardiovascular system, consisting of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of β-adrenoceptor agonists. No significant effects attributable to glycopyrronium were seen.

Animal reproduction studies with formoterol have shown a slightly reduced fertility in male rats at high systemic exposure and implantation losses, as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results have little relevance to man. A slight increase in the incidence of uterine leiomyomas has been observed in rats and mice treated with formoterol; an effect which is considered to be a class-effect in rodents after long-term exposure to high doses of β₂-adrenoreceptor agonists.

Animal reproduction studies with glycopyrronium have shown reduced rat and rabbit fetal weights, and low body weight gain of rat offspring before weaning was observed at considerably higher systemic exposures than those reached during clinical use. No evidence of carcinogenicity was seen in 2-year studies in rats and mice.