Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer

Br J Clin Pharmacol. 2010 Jun;69(6):637-44. doi: 10.1111/j.1365-2125.2010.03655.x.

Abstract

Aim: To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK).

Methods: An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 microm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 microg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K(+)) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min.

Results: The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K(+) revealed a significant dose-response with a non-significant T : R ratio.

Conclusions: The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 microg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adult
  • Albuterol / administration & dosage
  • Albuterol / analogs & derivatives*
  • Albuterol / pharmacokinetics
  • Androstadienes / administration & dosage
  • Androstadienes / pharmacokinetics*
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / pharmacokinetics*
  • Area Under Curve
  • Biological Availability
  • Creatinine / urine
  • Cross-Over Studies
  • Drug Combinations
  • Female
  • Fluticasone-Salmeterol Drug Combination
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / pharmacokinetics*
  • Humans
  • Hydrocarbons, Fluorinated
  • Hydrocortisone / urine
  • Male
  • Metered Dose Inhalers
  • Potassium / blood
  • Young Adult

Substances

  • Androstadienes
  • Anti-Asthmatic Agents
  • Drug Combinations
  • Fluticasone-Salmeterol Drug Combination
  • Glucocorticoids
  • Hydrocarbons, Fluorinated
  • Creatinine
  • Albuterol
  • Potassium
  • Hydrocortisone