Sarah Siederer

Metabolism and Disposition of Vilanterol, a Long-Acting β2-Adrenoceptor Agonist for Inhalation Use in Humans

The metabolism and disposition of vilanterol, a novel long-acting β2-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [14C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules—mainly related to the low chemical doses and complications associated with the inhalation route of administration.

Clinical Pharmacology of Cilomilast

Chronic obstructive pulmonary disease (COPD) is a multicomponent, chronic inflammatory disease of the lungs with systemic complications. The majority of the inflammation occurs in the peripheral airways and lung parenchyma. It is a progressive disease, leading to disability and eventual death, despite conventional therapy.Inflammatory activity can be reduced by increasing intracellular cyclic adenosine-3′,5′-monophosphate (cAMP) through inhibition of phosphodiesterase (PDE) IV, the principal PDE isoenzyme within pro-inflammatory cells, including eosinophils, mast cells, macrophages, lymphocytes, neutrophils and epithelial cells. PDE IV inhibition also has other effects, including relaxation of airway smooth muscle, suppression of smooth muscle mitogenesis and modulation of excitatory activity in pulmonary nerves.Cilomilast is a systemically available, second-generation, selective PDE IV inhibitor. It retains the therapeutic activity of the first-generation PDE IV inhibitors but lacks their profound emetic effect. Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD.Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits linear pharmacokinetics, with low between-subject variability. Cilomilast is highly protein bound (99.4%), but this binding is concentration-independent at clinically relevant doses, and it has a small volume of distribution at steady state (17L). Plasma clearance (approximately 2 L/h) is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours and steady state is rapidly achieved with twice-daily administration. The most abundant metabolite, formed by the action of cytochrome P450 2C8, has <10% of the activity of the parent molecule.Cilomilast pharmacokinetics in COPD patients were consistent with those in healthy subjects. Smoking, age and ethnicity had no clinically relevant effects. Total plasma cilomilast pharmacokinetic parameters did not change significantly with renal or hepatic impairment, but concentrations of unbound cilomilast increased with declining renal or hepatic function. Cilomilast had no clinically relevant interactions with a range of drugs likely to be coadministered to patients with COPD, with the exception of erythromycin where concurrent administration with cilomilast was associated with an increased incidence of gastrointestinal adverse events, a pharmacodynamic interaction predicted by their secondary pharmacology.Nausea was the principal adverse reaction seen in healthy subjects taking cilomilast, but this was reduced by administration with food or by use of simple dose-escalation regimens. Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline.Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD. It is generally well tolerated and has not generated safety concerns in any clinical study.

Population pharmacokinetics of inhaled fluticasone furoate and vilanterol in adult and adolescent patients with asthma.

OBJECTIVES Population pharmacokinetic (PK) methods were used to characterize the PK of fluticasone furoate (FF) and vilanterol (VI) in patients with asthma following once daily inhaled FF/VI and FF and to identify significant covariates that impact the PK. MATERIALS AND METHODS Four of the five studies in the meta-analysis were conducted in patients with asthma (> 90%), the fifth in healthy subjects. FF data were described by a two-compartment model with first order absorption and elimination. VI data were described by a three-compartment model with zero-order absorption and first order elimination. RESULTS Race was a significant covariate on inhaled clearance (CL/F) of FF PK. AUC(0-24) for Asian patients was on average 33 - 53% higher than for non-Asians. Race was also a significant covariate on VI PK, with lower (81%) central volume of distribution (Vc/F) for Asian patients compared with non-Asians; VI C(max) was 220 - 287% higher in Asian patients. Treatment (combination or monotherapy), predicted percentage FEV(1), and other demographic variables did not influence the PK of FF or VI. CONCLUSIONS Combination of FF/VI does not appear to affect the PK of FF or VI. The effect of race on PK of FF or VI does not have impact on dosage adjustments for FF/VI in East Asian patients with asthma.

P238 A randomised, double-blind (sponsor-unblind), placebo controlled, cross-over study to investigate the efficacy, effect on cough reflex sensitivity, safety, tolerability and pharmacokinetics of inhaled GSK2339345 in patients with chronic idiopathic cough using an aqueous droplet inhaler

Introduction and objectives Voltage gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in the afferent sensory nerve fibres innervating the airways responsible for evoking cough. Therefore a VGSC inhibitor may be an effective anti-tussive agent, inhibiting cough irrespective of the type of stimuli. We aimed to investigate the efficacy of a novel use-and frequency-dependent VGSC inhibitor (GSK2339345) in patients with chronic idiopathic cough. Methods We performed a two-part randomised, double-blind, placebo-controlled, cross-over study recruiting patients with chronic idiopathic cough from two specialist clinics. In the first part of the study, patients were randomly assigned to receive two inhaled doses of either GSK2339345 or placebo, 4 h apart during three study periods. The primary endpoint was the objective cough frequency (VitaloJAK, Vitalograph Ltd) during the 8 h post-treatment (4 hrs following each dose). The difference between GSK2339345 and placebo in log-transformed cough counts was investigated using a mixed effects model with fixed effects terms for treatment and period, and subject fitted as a random effect. In the second part, subjects attended on four study days, and underwent full dose-response cough challenges with capsaicin and citric acid following single doses of GSK2339345 or placebo. This was analysed using dose response modelling. Results Of 16 patients enrolled (56.7 ± 9.6 yrs; 13 female), 11 completed the study. Eight hour cough counts showed a 26% increase in cough counts with GSK2339345 vs placebo. However, on exclusion of the coughs occurring within 2 min of inhalation of the study drug, there was only a 1.6% increase in coughs; see Table 1 for ratio of adjusted geometric means. There appeared to be no impact of GSK2339345 on either of the cough challenges however, the dataset was too small to draw definitive conclusions.Abstract P238 Table 1 Endpoint Treatment Adjusted geometric mean Ratio of adjusted geometric means (90% credible intervals) % Increase from placebo 8 h cough count GSK2339345 192.5 1.26 (1.10, 1.44) 26% Placebo 152.7 8 h cough count excluding transient coughs GSK2339345 153.9 1.02 (0.87, 1.19) 1.6% Placebo 151.5 Based on data from 14 subjects – 21 8h counts per treatment due to replicate period. Transient coughs are the number of coughs occurring in the first 2 min following each dose. Conclusion There was no evidence of an anti-tussive effect of GSK2339345 over the 8 h analysis for any subject, despite cough frequency being highly reproducible within patients. Inhalation of GSK2339345 had a pro-tussive effect in all subjects following actuation of the device, not seen with placebo. The novel cough challenge methodology warrants further investigation as a development tool.