Effect of intranasal triamcinolone acetonide on basal hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis.

Intranasal corticosteroids are the most effective medication class for controlling allergic rhinitis (AR) symptoms. However, limited data are available on their effects on basal hypothalamic-pituitary-adrenal (HPA) axis function in children. This study was designed to determine the effect of 6-week triamcinolone acetonide aqueous (TAA-AQ) nasal spray treatment on HPA axis function by measuring 24-hour serum cortisol area under the curve (AUC(0-24h)) in children with AR aged 2-11 years. This phase 4, multicenter, double-blind, placebo-controlled, parallel-group study randomized children with AR to receive TAA-AQ (110 µg, 2-11 years old, or 220 µg, 6-11 years old) or placebo. At pre- and posttreatment domiciled visits, 24-hour serum cortisol and reflective total nasal symptom scores (rTNSSs) were assessed. Safety assessment included treatment-emergent adverse events (TEAEs) at each visit and trough levels of 24-hour serum cortisol. A total of 140 subjects (mean age, 7.2 years; males, 59%) were randomized; 66 from each group completed treatment. The ratio of TAA-AQ to placebo for change from baseline in serum cortisol AUC(0-24h) was 0.966 (95% confidence interval, 0.892-1.045). Reduction from baseline in mean rTNSS was significantly greater in the TAA-AQ than in the placebo group (difference: least square mean ± SE = -0.85 ± 0.24; p = 0.0007). The safety profile was similar (TEAEs, TAA-AQ, 27.5%; placebo, 25.4%), and so was the mean change in serum cortisol trough level (TAA-AQ, -0.4 µg/dL; placebo, -0.1 µg/dL; p = 0.1818 for treatment difference) from pre- to posttreatment. TAA-AQ was safe, well tolerated, and not associated with clinically meaningful suppression of serum cortisol AUC(0-24h) in children with AR. Clinical trial NCT01154153, www.clinicaltrials.gov.

Assessment of potential pharmacokinetic interactions of ezetimibe/simvastatin and extended-release niacin tablets in healthy subjects.

BACKGROUND: Efforts to lower plasma lipid levels sometimes require multiple agents with different mechanisms of action to achieve results specified by national treatment guidelines. METHODS: This was an open-label, randomized, three-period, multiple-dose crossover study that assessed the potential for pharmacokinetic interaction between extended-release niacin and ezetimibe/simvastatin and their major metabolites. Eighteen adults received three randomized treatments: (A) extended-release (ER) niacin 1000 mg/day for 2 days, followed by 2000 mg/day for 5 days; (B) ezetimibe/simvastatin 10 mg/20 mg/day; (C) coadministration of Treatments A and B. Treatments were given once a day after a low fat breakfast for a total of 7 days, with a 7-day inter-dose period. RESULTS: There were small (mean ≤35%) increases in drug exposure for all analytes after coadministration of ER niacin and ezetimibe/simvastatin 10 mg/20 mg. The least-square mean between treatment C(max) (maximum plasma concentration) ratios (×100) were 97, 98, and 109% for ezetimibe, simvastatin and niacin, respectively. The corresponding ratios for total ezetimibe, simvastatin acid, and nicotinuric acid were 99, 118, and 110%. The AUC((0-24)) (area under the plasma concentration-time curve from time zero to 24 h after dosing) ratios for ezetimibe, simvastatin, and niacin were 109, 120, and 122%, respectively, and the corresponding ratios for total ezetimibe, simvastatin acid, and nicotinuric acid were 126, 135 and 119%. CONCLUSION: There is a small pharmacokinetic drug interaction between ER niacin and ezetimibe/simvastatin and although this is not considered to be clinically significant, the concomitant use of these drugs should be appropriately monitored, especially during the niacin titration period.

Systemic exposure and urinary cortisol effects of fluticasone propionate formulated with hydrofluoroalkane in 4- to 11-year-olds with asthma.

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.

Evaluation of the safety and efficacy of levalbuterol in 2-5-year-old patients with asthma.

The purpose of this study was to evaluate the safety and efficacy of single-isomer (R)-albuterol (levalbuterol, LEV) in children aged 2-5 years. Children aged 2-5 years (n = 211) participated in this multicenter, randomized, double-blind study of 21 days of t.i.d. LEV (0.31 mg or 0.63 mg without regard to weight), racemic albuterol (RAC, 1.25 mg for children <33 pounds (lb); 2.5 mg for children >/=33 lb), or placebo (PBO). Endpoints included adverse-event (AE) reporting, safety parameters, peak expiratory flow (PEF), the Pediatric Asthma Questionnaire(c) (PAQ), and the Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ). Baseline disease severity was generally mild in all groups, as defined by PAQ scores that ranged from 6.3-7.3 on a scale of 0-27 and 1.5 days/week of uncontrolled asthma. After treatment, the PAQ decreased in all groups (P = NS). In the subset of subjects able to perform PEF (51.7%), all active treatments improved in-clinic PEF after the first dose (mean +/- SD: PBO, 1.4 +/- 20.8; LEV 0.31 mg, 12.4 +/- 12; LEV 0.63 mg, 16.7 +/- 15.4; RAC, 18.0 +/- 16.5 l/min; P < 0.01). PACQLQ measurements improved more than the minimally important difference only in the LEV-treated groups, and were significant in children <33 lb (P < 0.05). Asthma exacerbations occurred primarily in children >/=33 lb, and one serious asthma exacerbation occurred in the 2.5-mg RAC group. RAC and LEV 0.63 mg, but not LEV 0.31 mg or placebo, led to significant increases in ventricular heart rate. In this study of levalbuterol in children aged 2-5 years with asthma, LEV was generally well-tolerated, and in children able to perform PEF, led to significant bronchodilation compared with placebo.

Lack of racial differences in the pharmacokinetics of subcutaneous golimumab in healthy Japanese and Caucasian male subjects.

This phase 1 study evaluated the single-dose pharmacokinetics and safety of subcutaneous golimumab, a human anti-tumor necrosis factor-alpha monoclonal antibody, in healthy Japanese and Caucasian subjects. Eligible subjects were males, aged 20 to 45 years, weighing 50 to 90 kg with a body mass index of 19 to 30 kg/m(2). Japanese and Caucasian subjects were matched by body weight and dose group. Blood samples were collected through day 50 following a single subcutaneous injection of golimumab 50 or 100 mg. The pharmacokinetic parameters were determined using a noncompartmental method. All 51 subjects (24 Japanese, 27 Caucasian) were included in the safety analysis; 47 completed the study and were included in the pharmacokinetic analysis. The pharmacokinetics of golimumab were comparable in both race groups. Peak concentrations were observed approximately 4 to 6 days after administration. No significant differences in exposure or mean half-life (range, 11-13 days) were observed between Japanese and Caucasian subjects at the same dose level. Regardless of race, serum golimumab exposure increased with increasing dose. Mean apparent clearance ranged from 12 to 19 mL/kg/d. Mean apparent volume of distribution (224-262 mL/kg) remained constant with an increase in dose. No antibodies to golimumab were detected. Single subcutaneous injections of golimumab 50 mg or 100 mg were generally well tolerated in these healthy male Japanese and Caucasian subjects.

Nebulized formoterol fumarate: Dose selection and pharmacokinetics.

To determine a dose of nebulized formoterol fumarate inhalation solution (FFIS) comparable to that of the marketed formoterol fumarate dry powder inhaler (FA, 12microg), two crossover studies were conducted in subjects with COPD. Study 1 was a single-dose, double-blind, double-dummy dose-ranging study in which 47 subjects were randomly assigned to treatment sequences that evaluated the bronchodilatory effects of FFIS 2.5, 5, 10, 20, and 40microg, FA, and placebo over 12h. Mean FEV(1) AUC(0-12) following FFIS treatment ranged from 1.3 to 3.0l/h in a dose-related manner, with equivalent values (2.3l/h) for FFIS 20microg and FA. Results for other spirometric measures, including peak and trough FEV(1) and absolute change in FEV(1) by timepoint, confirmed the comparability of FFIS 20microg and FA. Study results with the nebulized formulation supported the rapid time to onset of bronchodilation with FFIS 20microg (3.9 and 2.2min imputed for 15% and 12%/200ml response, respectively). Study 2, a single-dose, open-label crossover study, was conducted to establish the pharmacokinetic (PK) profile of nebulized formoterol and confirm comparability to FA. Thirteen subjects were randomly assigned to treatment sequences with FFIS 10, 20, and 244microg and FA with a 5-14-day washout period between each treatment. Formoterol levels were assessed from blood and urine collected pre-dose and over a 24-36-h period after dosing. Pharmacodynamic (PD) measures included clinical laboratory and ECG measures pre-dose and over a 24-h period post-dose. FFIS 244mug was rapidly absorbed with a T(max) of 12min and t(1/2) of 6.1h. Data from other doses were sporadic due to assay sensitivity. The mean amount excreted (Ae) in urine suggested linear kinetics and confirmed the comparability of FFIS 20microg and FA. Mean serum potassium decreased and mean serum glucose increased transiently in a dose-dependent manner following treatment. No clinically significant ECG changes were observed; mean heart rate increased after treatment with FFIS 244mug by up to 6bpm. Findings from dose-ranging and PK/PD studies confirmed that a 20microg dose of FFIS was comparable to formoterol fumarate delivered by dry powder inhalation (12microg) and established the dose proportionality and linear kinetics of formoterol fumarate delivered by nebulization.

Efficacy and safety of inhaled fluticasone propionate chlorofluorocarbon in 2- to 4-year-old patients with asthma: results of a double-blind, placebo-controlled study.

BACKGROUND: Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler (MDI) with a holding chamber as the preferred therapy for young children with asthma. OBJECTIVE: To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma. METHODS: Randomized, double-blind, placebo-controlled, parallel-group study of 332 children aged 24 to 47 months with asthma. Fluticasone propionate chlorofluorocarbon, 44 or 88 microg twice daily, or placebo (chlorofluorocarbon propellant alone) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask. The primary efficacy measure was average change in 24-hour daily asthma symptom scores. Safety assessments included adverse events, 12-hour urinary cortisol excretion, and growth. RESULTS: Treatment failure (ie, asthma exacerbation) occurred in approximately half as many fluticasone propionate-treated patients (13%-14%) as placebo-treated patients (24%). Compared with placebo users, patients treated with fluticasone propionate, 88 microg twice daily, had a 13% greater improvement in the mean proportion of symptom- and albuterol-free days (P = .02); asthma symptom scores and albuterol use were also significantly reduced. Patients treated with fluticasone propionate, 44 microg twice daily, had greater improvements than placebo-treated patients; however, differences did not reach statistical significance. At end point, the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients. No clinically relevant changes in 12-hour overnight urinary cortisol excretion were observed. CONCLUSION: Compared with placebo use, fluticasone propionate, 88 microg administered twice daily, significantly reduced asthma exacerbations, asthma symptoms, and rescue albuterol use and was well tolerated, with no clinically relevant systemic effects, as measured by growth velocity or 12-hour urinary cortisol excretion levels.

Use of 0.06% ipratropium bromide nasal spray in children aged 2 to 5 years with rhinorrhea due to a common cold or allergies.

BACKGROUND: Rhinorrhea from common colds or allergies in children is similar to that in adults, yet there are few data on the use of ipratropium bromide nasal spray in children younger than 5 years. OBJECTIVE: To evaluate the safety and efficacy of 0.06% ipratropium bromide nasal spray in 2- to 5-year-old children with rhinorrhea from a common cold or allergies. METHODS: A total of 230 children (43 with common colds and 187 with allergies) participated in an open-label, multicenter study. Patients with a common cold received ipratropium bromide nasal spray (84 microg per nostril) 3 times daily for 4 days; those with allergies received ipratropium bromide nasal spray (42 microg per nostril) 3 times daily for 14 days. RESULTS: In the common cold and allergy groups, 91% and 90% of the parents, respectively, found that ipratropium bromide was either "very useful" or "somewhat useful." Furthermore, 67% and 91% of parents in the common cold and allergy groups, respectively, found that administration of a nasal spray was either "extremely easy" or "very easy." Symptom scores were improved from baseline in both groups. The nasal spray was well tolerated and was not associated with serious or systemic anticholinergic adverse effects. Most adverse events were infrequent and mild to moderate, and study discontinuation due to an adverse event occurred in less than 3% of patients. CONCLUSIONS: The 0.06% ipratropium bromide nasal spray, 42 or 84 microg per nostril 3 times daily, is easy to administer, safe, and effective for the control of rhinorrhea in children aged 2 to 5 years with a common cold or allergies.

Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis.

BACKGROUND: Intranasal corticosteroids are safe and effective for treating allergic rhinitis in adults. Since children may receive more systemic corticosteroid on a dose-per-weight basis than adults, the safety of corticosteroid therapy in pediatric patients is an important issue. OBJECTIVE: To determine the effects of treatment with budesonide aqueous nasal spray using the recommended once-daily dose for adults and children 6 years and older on hypothalamic-pituitary-adrenal (HPA) axis function in pediatric patients with allergic rhinitis. METHODS: In a 6-week, multicenter, double-blind, placebo-controlled study, 78 patients aged 2 to 5 years with allergic rhinitis were treated with budesonide aqueous nasal spray (64 microg/d) or placebo. Mean change in morning plasma cortisol levels from baseline to study end 0, 30, and 60 minutes after low-dose (10-microg) cosyntropin stimulation and mean change in the difference from 0 to 30 minutes and from 0 to 60 minutes after cosyntropin stimulation were used to evaluate HPA axis function. RESULTS: Mean change from baseline to study end in plasma cortisol levels 0, 30, and 60 minutes after cosyntropin stimulation and the difference from 0 to 30 minutes and from 0 to 60 minutes were not significantly different between the treatment and placebo groups (P > .05 for all). At the end of the study, 3 budesonide aqueous nasal spray and 6 placebo patients were classified as having subnormal HPA axis function. The safety and tolerability profile of budesonide aqueous nasal spray was comparable to that of placebo. CONCLUSIONS: Administration of budesonide aqueous nasal spray for 6 weeks was well tolerated and safe and had no measurable suppressive effects on HPA axis function in patients aged 2 to 5 years with allergic rhinitis.