At an exposure from formoterol fumarate dry powder formulation comparable to approximately 12-fold the recommended dose of PERFOROMIST Inhalation Solution, a mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose in healthy subjects. This study showed that the maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett's correction and was 8 msec when calculated using Fridericia's correction. The QTc returned to baseline within 12 to 24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on pulse rate and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at this supratherapeutic formoterol fumarate inhalation dose.

Tachyphylaxis / Tolerance

Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In a placebo-controlled clinical trial in 351 adult patients with COPD, the bronchodilating effect of PERFOROMIST Inhalation Solution was determined by the FEV₁ area under the curve over 12 hours following dosing on Day 1 and after 12 weeks of treatment. The effect of PERFOROMIST Inhalation Solution did not decrease after 12 weeks of twice-daily treatment (Figures 1 and 2).

Pharmacokinetics

Information on the pharmacokinetics of formoterol (dry powder and/or inhalation solution) in plasma and/or urine is available in healthy subjects as well as patients with chronic obstructive pulmonary disease after oral inhalation of doses at and above the therapeutic dose.

Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

Absorption

Pharmacokinetic properties of formoterol fumarate were evaluated in 12 COPD patients following inhalation of single doses of PERFOROMIST Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) and 12 mcg formoterol fumarate dry powder, through 36 hours after single-dose administration. Formoterol fumarate concentrations in plasma following the 10 and 20 mcg doses of PERFOROMIST Inhalation Solution and the 12 mcg dose of formoterol fumarate dry powder were undetectable or only detected sporadically at very low concentrations. Following a single 244 mcg dose of PERFOROMIST Inhalation Solution (approximately 12 times the recommended clinical dose), formoterol fumarate concentrations were readily measurable in plasma, exhibiting rapid absorption into plasma, and reaching a maximum drug concentration of 72 pg/mL within approximately 12 minutes of dosing.

The mean amount of formoterol excreted unchanged in 24 hour urine following single oral inhalation doses of 10, 20, and 244 mcg PERFOROMIST Inhalation Solution were found to be 109.7 ng, 349.6 ng, and 3317.5 ng, respectively. These findings indicate a near dose proportional increase in systemic exposure within the dose range tested.

When 12 mcg of a dry powder formulation of formoterol fumarate was given twice daily to COPD patients by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 to 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. Although multiple-dose pharmacokinetic data is unavailable from PERFOROMIST Inhalation Solution, assumption of linear pharmacokinetics allows a reasonable prediction of minimal accumulation based on single-dose pharmacokinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.

Distribution

The binding of formoterol to human plasma proteins in vitro was 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 244 mcg dose of PERFOROMIST Inhalation Solution.

Metabolism

Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. In vitro studies showed that multiple drug-metabolizing enzymes catalyze glucuronidation (UGT1A1, 1A8, 1A9, 2B7 and 2B15 were the most predominant enzymes) and O-demethylation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.

Excretion

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