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

Seretide (GlaxoSmithKline, UK) is a combination inhaler which contains both fluticasone (FP) and salmeterol (SM).

A generic fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) has recently been developed.

Determination of therapeutic equivalence is essential in the development of generic products.

WHAT THIS STUDY ADDS

This paper determines that in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes.

This paper shows that the generic and reference products were equivalent in terms of FP, but not SM pharmacokinetics.

No significant differences were found between generic and reference products in terms of either adrenal suppression or hypokalaemia.

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 mu m). 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 mu g 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 mu g 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.