ATIMOS MODULITE Pressurised inhalation solution Ref.[6862] Active ingredients: Eformoterol

Absorption

As with other substances administered by inhalation, 90% of the inhaled formoterol dose is swallowed and absorbed from the gastrointestinal tract. The pharmacokinetic characteristics of the oral formulation can thus be extrapolated to the inhalation of metered aerosol.

Absorption is both rapid and extensive; after inhalation of a therapeutic dose (12 micrograms) of Atimos Modulite pressurised inhalation solution in asthmatic patients, the peak plasma concentration is observed approximately 15 minutes after inhalation, earlier than that observed with a formoterol powder inhalation. Generally, absorption rate should be taken into account when switching patients from one formoterol formulation to another.

Absorption of formoterol is linear following inhalation of 12 micrograms to 96 micrograms of formoterol fumarate dihydrate.

Oral doses of up to 300 micrograms of formoterol are rapidly absorbed from the gastrointestinal tract. The peak plasma concentration of the unchanged substance is reached after 30 minutes to 1 hour. More than 65% of an oral dose of 80 micrograms is absorbed.

Dose linearity is present within a dose range of 20 micrograms to 300 micrograms (oral administration).

Repeated daily administration of 40-160 micrograms per day does not result in accumulation because of the short half-life. The pharmacokinetics of formoterol do not differ significantly between men and women.

Distribution

Plasma protein binding is 61% to 64% (34% to albumin); binding sites are not saturated at therapeutic dose levels.

Biotransformation

Formoterol is metabolised primarily via direct glucuronisation and is eliminated completely. A further route of biotransformation is O-demethylation followed by glucuronisation with consecutive complete elimination.

Multiple CYP450 isozymes catalyze the transformation (2D6, 2C19, 2C9, and 2A6) and consequently the potential for metabolic drug-drug interaction is low. The kinetics of formoterol are similar after single and repeated administration, indicating no auto-induction or inhibition of metabolism.

Elimination

The elimination of formoterol apparently follows a polyphasic pattern, and the half-life described is therefore dependent on the time intervals considered. Based on plasma or blood concentrations measured 6, 8 or 12 h after oral administration, an elimination half-life of 2 to 3 hours was determined. A half-life of 5 hours was calculated from the renal excretion rate between 3 and 16 h after inhalation.

The active substance and metabolites are eliminated completely, two thirds of an oral administered dose with the urine, one third with the faeces. Following inhalation of formoterol, a mean of 6% to 9% of the substance is eliminated unchanged with the urine. Renal clearance of formoterol is 150ml/min.

The effects of formoterol in rats and dogs were largely confined to the cardiovascular system and consisted of known pharmacological manifestations of high β₂-agonist doses.

A somewhat reduced fertility in male rats was observed at very high systemic exposure of formoterol.

No genotoxic effects of formoterol have been observed in in-vitro or in-vivo tests. In rats and mice, a slight increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class effect in rodents after long exposure to high doses of β₂-agonists.