Bronchodilator effects, pharmacokinetics and safety of PSX1002-GB, a novel glycopyrronium bromide formulation, in COPD patients; a randomised crossover study.

AIMS: To establish the dose-response relationship for pharmacodynamics (bronchodilatation), safety and pharmacokinetics of a novel particle engineered formulation of Glycopyrronium bromide (PSX1002-GB) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with moderate to severe COPD with bronchodilator reversible lung function were enrolled into this randomized, placebo-controlled, double-blind, dose-ranging, single dose, five way cross-over study (n = 37). Patients received single doses of PSX1002-GB (12.5-100 µg) via pMDI with one-week washouts between treatments. RESULTS: PSX1002-GB caused a bronchodilator response observed at 5 min post-dose at all doses. Significant improvements in mean change from baseline FEV1 at 24 h were seen at all doses compared with placebo; Mean changes were 0.071L (95% CI 0.041-0.101), 0.087L (95% CI 0.056-0.118), 0.102L (95% CI 0.072-0.133) and 0.120L (95% CI 0.089-0.150) for 12.5, 25, 50 and 100 µg respectively. PSX1002-GB 50 and 100 mcg caused rapid bronchodilation at 5 min after dosing. PSX1002-GB was well tolerated with similar adverse event rates reported compared to placebo. There were no clinically relevant changes in heart rate, blood pressure or ECG parameters (including QTc interval). CONCLUSION: Single doses of PSX1002-GB (12.5-100 µg) were well tolerated. PSX1002-GB 50 and 100 mcg delivered by pMDI produced rapid onset bronchodilation that was sustained over a 24 h period.

Absolute bioavailability of intranasal fluticasone furoate in healthy subjects.

BACKGROUND: Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS: A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.

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.