Relationship of arachidonic acid concentration to cyclooxygenase-dependent human platelet aggregation.

Inhibition of ex vivo arachidonic acid (AA)-induced aggregation is a biomarker for the isotype selectivity of cyclooxygenase (COX) inhibitors since platelets express COX-1 but not COX-2. At low concentrations, there is broad inter- and intrasubject variability in AA-induced aggregation of platelets ex vivo. This study defined a concentration that reliably induces aggregation without overcoming inhibition by therapeutic aspirin therapy (ASA, 81-mg) treatment. Logistic regression analysis of ex vivo aggregation, induced with increasing concentrations of AA in platelet-rich plasma (PRP), estimated that platelets from > or = 90% of subjects would aggregate at > or = 1.5 mM AA (95% confidence interval [CI], 1.1, 2.1). A concentration of 1.6 mM AA failed to aggregate platelets from 26 healthy volunteers, who had previously aggregated at this concentration, following six daily oral doses of 81 mg of ASA. These data demonstrate that 1.6 mM AA reproducibly induces platelet aggregation in PRP from healthy volunteers without overcoming the antiplatelet effect of daily low-dose aspirin therapy.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate, a novel inhaled corticosteroid, in children aged 5-11 years with persistent asthma: A randomized trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate (FF) in children (5-11 years) with persistent asthma. Twenty-seven children received inhaled FF 100 µg or placebo via the ELLIPTA™ dry powder inhaler once daily for 14 days, with a ≥7 day washout period. Adverse events (AEs) were reported by eight (31%) and four (16%) subjects during FF 100 µg and placebo treatment, respectively. Headache was reported by three subjects during FF 100 µg treatment and by no subjects during placebo treatment, all other AEs were reported by only one subject on either treatment; there were no serious AEs. Following repeat dosing, the arithmetic mean (SD) FF Cmax was 26.71 pg/mL (9.16) at 31 minutes post-dose. Arithmetic mean (SD) FF AUC(0-t) was 121.44 pg h/mL (83.04). Arithmetic mean values for weighted mean (SD) serum cortisol (0-12 hours) on day 14 were 56.49 (16.51) and 67.57 (20.66) ng/mL for FF 100 µg and placebo, respectively. No clinically significant effect of FF on serum cortisol levels was observed. FF was well tolerated. Pharmacokinetic profiles were well defined and did not differ between age groups in the study population, and no clinically significant suppression of serum cortisol was observed.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting ß-Agonist, in Children Aged 5-11 Years with Persistent Asthma: A Randomized Trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 µg in children aged 5-11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well-tolerated and no long-acting ß2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5-11 years.

Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma.

BACKGROUND: Asthma is a chronic disease afflicting millions of children worldwide. Short-acting ß2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting ß2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting ß2-agonist. OBJECTIVE: We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting ß2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma. METHODS: In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14. RESULTS: Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS: Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.