Brovana (arformoterol tartrate); 慢性阻塞性肺疾病的治疗 Sepracor公司生产; 2006年10月批准；

CLINICAL PHARMACOLOGY
Mechanism of Action
Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta2-agonist than the (R,R)-enantiomer. While it is recognized that beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, data indicate that there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including arformoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Animal Pharmacology

In animal studies investigating its cardiovascular effects, arformoterol induced dose-dependent increases in heart rate and decreases in blood pressure consistent with its pharmacology as a beta-adrenergic agonist. In dogs, at systemic exposures higher than anticipated clinically, arformoterol also induced exaggerated pharmacologic effects of a beta-adrenergic agonist on cardiac function as measured by electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs).

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics

The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and chronic obstructive pulmonary disease (COPD) patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg.

Absorption

In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (Cmax) and systemic exposure (AUC0-12h) were 4.3 pg/mL and 34.5 pg*hr/mL, respectively. The median steady-state peak (R,R)-formoterol plasma concentration time (tmax) was observed approximately one half hour after drug administration.

Systemic exposure to (R,R)-formoterol increased linearly with dose in COPD patients following arformoterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks.

In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate inhalation powder (Foradil® Aerolizer™) was administered twice daily for 2 weeks, the accumulation index was approximately 2.5 based on the plasma (R,R)-formoterol concentrations in all three treatments. At steady state, geometric means of systemic exposure (AUC0-12h) to (R,R)-formoterol following 15 mcg of arformoterol inhalation solution and 12 mcg of formoterol fumarate inhalation powder were 39.33 pg*hr/mL and 33.93 pg*hr/mL, respectively (ratio 1.16; 90% CI 1.00, 1.35), while the geometric means of the Cmax were 4.30 pg/mL and 4.75 pg/mL, respectively (ratio 0.91; 90% CI 0.76, 1.09).

In a study in patients with asthma, treatment with arformoterol 50 mcg with pre- and post-treatment with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC0-6h by 27% and Cmax by 23% as compared to treatment with arformoterol 50 mcg alone. This suggests that a substantial portion of systemic drug exposure is due to pulmonary absorption.

Distribution

The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. The concentrations of arformoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of multiple doses of 50 mcg arformoterol.

哮喘是一种常见慢性病，据WHO估计，全球哮喘病患者高达2.75亿人。近十年，哮喘症的发病率和死亡率成上升趋势，每年有超过18万人死于哮喘。目前我国哮喘病的发病率为1﹪，儿童发病率为3-5﹪，较十年前有明显增加。

酒石酸阿福莫特罗的上一代产品消旋体福莫特罗的原料药和片剂由日本山之内制药公司开发，1985年8月在日本上市(商品名Atock)。

酒石酸阿福特罗吸入液

2006年10月7日，美国FDA批准塞普拉柯(Sepracor)公司的酒石酸阿福特罗(arformoterol tartrate)吸入液15μg(商品名：Brovana)上市，作为长期用药一日2次(早晚各一次)维持治疗慢性阻塞性肺病引起的支气管收缩。本品仅供喷雾使用。Brovana是首个获准采用喷雾器喷雾药液的长效β2激动剂，吸入器将药液转化成细雾滴，经吸嘴吸入肺部。

塞普拉柯公司完成了Brovana 100多项临床前和总共2 000例患者的16项临床研究。在临床研究中进行了2项12周关键的研究，项700多一例患者和另一项800例患者12个月的安全性研究。在Ⅲ期临床研究中，以Brovana治疗的患者测定的肺功能FEV1较安慰剂在统计学上显著改善。Brovana 15μg一日2次给药后12小时(FEV1 AUC0-12)较安慰剂显著改善支气管扩张。此改善保持了12周的研究期。给与首剂Brovana 15μg后，以FEV1增加15％为起效时间出现在6.7分钟。当FEV1定为12％和200mL时，支气管扩张的起效时间为给药后的20分钟。给药后1～3小时通常可见到支气管扩张的最大作用。