le 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
Following administration of single 10, 20, and 244 mcg PERFOROMIST Inhalation Solution doses (calculated on an anhydrous basis) delivered via nebulizer in 12 COPD patients, on average, about 1.1% to 1.7% of the dose was excreted in the urine as unchanged formoterol as compared to about 3.4% excreted unchanged following inhalation administration of 12 mcg of formoterol fumarate dry powder. Renal clearance of formoterol following inhalation administration of PERFOROMIST Inhalation Solution in these subjects was about 157 mL/min. Based on plasma concentrations measured following the 244 mcg dose, the mean terminal elimination half-life was determined to be 7 hours.
Gender
As reported for another formoterol fumarate inhalation formulation, upon correction for body weight, pharmacokinetics of formoterol fumarate did not differ significantly between males and females.
Geriatric, Pediatric, Hepatic/Renal Impairment
The pharmacokinetics of formoterol fumarate has not been studied in elderly and pediatric patient populations. The pharmacokinetics of formoterol fumarate has not been studied in subjects with hepatic or renal impairment.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityThe carcinogenic potential of formoterol fumarate has been eva luated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study (AUC exposure approximately 2300 times human exposure at the maximum recommended daily inhalation dose), but not at dietary doses up to 5 mg/kg (AUC exposure approximately 570 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg (AUC exposure was approximately 57 times human exposure at the maximum recommended daily inhalation dose) and above. This finding was not observed in the drinking water study, nor was it seen in mice (see below).
In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg (AUC exposure approximately 1000 times human exposure at the maximum recommended daily inhalation dose) and above in the drinking w |
