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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
Author(s) -
Möllmann Helmut,
Wagner Melanie,
Krishnaswami Sriram,
Dimova Hristina,
Tang Yufei,
Falcoz Christine,
DaleyYates Peter T.,
Krieg Michael,
Stöckmann Ricarda,
Barth Jürgen,
Lawlor Ms. Caroline,
Möllmann Anja C.,
Derendorf Hartmut,
Hochhaus Günther
Publication year - 2001
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700122012913
Subject(s) - fluticasone propionate , pharmacokinetics , budesonide , medicine , pharmacodynamics , inhalation , dosing , fluticasone , dry powder inhaler , crossover study , placebo , pharmacology , anesthesia , corticosteroid , asthma , inhaler , alternative medicine , pathology
Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare the PK/PD properties of clinically equivalent, single, and multiple doses of dry‐powder formulations of inhaled fluticasone propionate (FP, 200 and 500 μg via Diskus®) and budesonide (BUD, 400 and 1000 μg via Turbohaler®). Fourteen healthy subjects completed a double‐blind, doubledummy, randomized, placebo‐controlled, five‐way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice‐daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/mass spectrometry assays. The 24‐hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes after inhalation of FP with no influence of dose or dosing regimen. After a single dose of 1000 vg BUD and 500 Vg FP, the median estimates of terminal half‐life and mean residence time were3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP, respectively. On average, the area underthe curve (AUC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12‐hour period following the first dose on day 1, whereas AUC estimates were 50% to 80% higher for FP at steady state, indicating accumulation. However, the steady‐state C max values were seven to eight times and AUC values three to four times higher for BUD than for FP Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 μg dose and 36% for the 1000 μg dose). For FP, only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 g dose and 27% forthe 500 μg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice‐daily doses in healthy subjects, the systemic effects of FP delivered via Diskus® on AUC 24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler®.