A Study Comparing the Clinical Pharmacokinetics, Pharmacodynamics, and Tolerability of Triamcinolone Acetonide HFA‐134a Metered‐Dose Inhaler and Budesonide Dry‐Powder Inhaler following Inhalation Administration

Abstract

The impending phaseout of chlorofluorocarbons as propellants in pressurized metered-dose inhalers used in the treatment of asthma has resulted in the development of alternative devices to deliver drug to the pulmonary airways. These alternative devices include metered-dose inhalers using environmentally friendly hydroflurocarbon propellants and breath-actuated dry-powder inhalers. The purpose of this study was to compare the single- and multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of a newly developed hydroflurocarbon formulation of triamcinolone acetonide (Azmacort HFA 225 mcg Inhalation Aerosol) to that of the dry-powder formulation of budesonide (Pulmicort Turbuhaler 200 mcg). This three-way crossover study used 18 normal healthy subjects each receiving a 675 mcg dose of triamcinolone acetonide, 600 mcg dose of budesonide, or placebo twice a day for 5 days. Serial plasma samples were collected after the first and last dose of test medication for pharmacokinetic analysis. Pharmacodynamics were assessed by changes in hypothalamic-pituitary-adrenal axis function as measured by 8 a.m. serum cortisol, 24-hour overnight serum cortisol AUC(0-24), and 24-hour urinary-free cortisol after the last evening dose of test drug. Tolerability was assessed through physical examinations, vital signs, 12-lead ECG, routine clinical labs, and adverse events recording. Both compounds were systemically absorbed. However, no significant drug accumulation was noted with chronic dosing. Chronic dosing did result in a statistically significant 20% reduction in basal 24-hour serum cortisol AUC(0-24) for both compounds. There were no clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or routine clinical labs noted during the study. Overall, the study drugs were well tolerated, with adverse events characterized as mild to moderate in severity.

Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects

“…12 In the case of BUD, the 2.1-and 3.5-hour terminal half-lives observed for the two doses are consistent with a reported range of 2 to 3.5 hours. [25][26][27] The 1.5-to 1.8-fold accumulation observed for FP is in agreement with published data and in accordance with its long terminal half-life. 19,20,28 In the case of BUD, an up to 30% increase in AUC ss compared to AUC 0-12 on day 1 was observed, consistent with previously published reports in mild asthmatics.…”

“…During steady-state twice-daily dosing on day 5, the two doses caused 12% (4,20) and 27% (19,35) suppression, respectively. In the case of BUD, single doses of 400 and 1000 µg reduced the 24-hour cortisol levels by 4% (-6, 15) and 19% (10, 28) that increased on multiple dosing to 19% (10,27) and 36% (25,46), respectively. Results from pairwise multiple-comparison Tukey tests indicated statistically significant differences between the low-and high-dose effects of FP and similarly between those of BUD.…”

Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids' Effect on Hypothalamic–Pituitary–Adrenal Axis Function

“…A three‐way crossover, placebo‐controlled study comparing the tolerability a dry powder formulation of BUD (total daily dose of 1200 μg) to a HFA formulation of TAA (total daily dose of 1350 μg) was conducted by Argenti et al . in 18 normal healthy subjects.…”

Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids’ Effect on Hypothalamic-Pituitary-Adrenal Axis Function, Part I: General Overview of HPA Axis Study Design

“…For multiple comparisons among all treatment groups, analysis of covariance (ANCOVA) and analysis of variance (ANOVA) are commonly performed, adjusted for effects of possible covariates such as: baseline, age, sex, center, treatment, subject, and investigator. For pair wise comparisons, Dunnett's procedure was most often used to adjust for the comparisons of treatment groups with the placebo group . Pair wise comparisons can also be constructed and adjusted using the Fisher's exact test, Tukey–Kramer method, and two‐sided t ‐test .…”

“…For pair wise comparisons, Dunnett's procedure was most often used to adjust for the comparisons of treatment groups with the placebo group. 46,47,52,91 Pair wise comparisons can also be constructed and adjusted using the Fisher's exact test, 49 Tukey-Kramer method, 100 and two-sided t-test. 85 For crossover studies, a comparison is often made with assess any carryover effect between the two treatment periods by comparing values for placebo and washout in order of sequence.…”