Question

Brief 250 word essay on summarizing the pharmacokinectics, mechanism of action, and pharmacodynamics of the inaler Trelegy Ellipta.

Answer 1

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Trelegy Elliptacontains fluticasone furoate, umeclidinium, and vilanterol. These drugs represent three different classes of medications, each having different effects on clinical and physiological indices.

Fluticasone Furoate: It is a synthetic trifluorinated corticosteroid with potent, local, anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. Inflammation is an important component in the pathogenesis of COPD. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, basophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as NFkB resulting in inhibition of pro-inflammatory cytokines, and inhibition of antigen-induced lung eosinophilia in sensitized rats. These anti-inflammatory actions of corticosteroids may contribute to their efficacy. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. Although fluticasone furoate is structurally related to fluticasone propionate, they are distinct chemical entities and do not share common metabolites. In vitro studies have shown that translocation of the glucocorticoid receptor into the cell nucleus (essential for anti-inflammatory activity) is both more rapid and more prolonged with fluticasone furoate compared with fluticasone propionate. Nuclear localization of the glucocorticoid receptor was observed at 30 hours post-exposure with fluticasone furoate but not with fluticasone propionate. The clinical relevance of these findings is unknown.

Umeclidinium: Umeclidinium is a long-acting muscarinic antagonist (LAMA) [also referred to as a long-acting anticholinergic (LAAC)]. It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its 24-hour bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic acetylcholine receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Vilanterol: Vilanterol is a selective high-affinity long acting beta2-agonist (LABA), with bronchodilatory effects maintained for 24-hours. The pharmacologic effects of beta2-agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic3’,5’-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total betaadrenergic 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.

Pharmacodynamics

Time to Onset of Action In a study of fluticasone furoate/umeclidinium/vilanterol100/62.5/25 mcg once daily, serial spirometry measures were obtained from a subgroup of 203 subjects. On Day 1, 49% of subjects achieved an increase of 100 mL over baseline FEV1 at 15 minutes (time of first serial spirometry sample). Median time to onset of action was 26 minutes.