Daley-Yates & Parkins cite data comparing relative lung dose of fluticasone propionate/salmeterol combination (FP/SM) from dry power inhalers which are more flow rate and resistance dependent than pressurized metered dose inhalers (pMDIs), and as such are not pertinent to the interpretation of our data[1]. Daley-Yates & Parkins focus particularly on the extra fine particle fraction deposited on stages 6–7. For the in vitro data it is the overall fine particle dose (in µg) deposited on stages 3–7 (i.e. <4.7 µm) which will determine the total lung absorption profile and in this regard it is evident that the test : reference (T : R) ratios for the two formulations were clearly close to unity. With regard to deposition of extra fine particles on stages 6–7 one has to place any differences in the T : R ratios in the context of the overall fine particle dose. Thus for pMDI alone the relative deposition of FP on stages 6–7 as a proportion of the overall fine particle dose was 3.08% and 1.82% (i.e. a difference of 1.26%) for test and reference products, respectively, and with spacer was 2.98% and 1.67% (i.e. a difference of 1.31%). Corresponding values for SM were 7.38% and 1.31% with pMDI alone (i.e. a difference of 6.07%), 6.11% and 1.20% with spacer (i.e. a difference of 4.91%). An absolute difference between test and reference products in extra fine particle dose of SM amounting to 1.04 µg with pMDI and 1.0 µg with spacer (i.e. at the usual single dose of two puffs) is unlikely to be of any clinical relevance in terms of meaningful systemic adverse effects on potassium and heart rate when used at the standard recommended dose. Moreover in terms of bronchodilator efficacy since airway β2-adrenoceptors are mostly located centrally, the topical impact of such a small difference in extra fine particles would be rather irrelevant in terms of disease control for patients. Daley-Yates & Parkins also criticize our abbreviated 2 h sampling period for FP in study 2 suggesting we may have missed the true total lung exposure, along with possible effects on Cmax due to time delay by using multiple puffs via the spacer. For the FP moiety in study 1 over a 24 h sampling period using four puffs, the T : R ratio was 0.91 for Cmax while for AUC(0,last) the ratio was 1.05. The ratios from study 1 were similar to those obtained in study 2 also using four puffs, which were 1.11 for Cmax and 1.07 for AUC(0,2 h). Given that we employed a crossover design in study 2, any putative impact of delay would be the same for test and reference formulations. From a clinical view point one also has to bear in mind that in real life patients will inevitably not be using their inhaler correctly, such that any small differences in extra fine particle dose will become rather trivial. We were required for regulatory purposes to be able to show assay sensitivity and as such we had to use artificially high single doses of FP/SM in our study, whereas in everyday prescribing the recommended maximum single dose is two puffs which is taken twice daily. The administered single dose of eight puffs in study 2 was four fold higher than the usual recommended dose, such that any small differences in β2- adrenoceptor mediated response would become accentuated. To put this in context even at a high single dose of eight puffs the mean difference in maximal chronotropic response of 6.4 beats min–1 or in hypokalaemia of 0.09 mmol l–1 is not clinically relevant. Indeed at the usual single dose of two puffs one would not expect to see any detectable systemic β2-adrenoceptor mediated adverse effects, as this does not coincide with the steep part of the dose–response curve. Moreover as patients take FP/SM on a regular twice daily basis, β2-adrenoceptor down regulation, uncoupling and associated sub-sensitivity of response would occur, such that any small putative differences in potassium or heart rate response between test and reference formulations would be diminished [2]. Daley-Yates & Parkins are also incorrect in suggesting that overnight urinary cortisol/creatinine is insensitive for detecting adrenal suppression in response to FP, as this measure has consistently been shown to be a sensitive measure of HPA-axis suppression compared with other markers of basal or stimulated adrenal function [3–7]. Thus, we stand firmly by our conclusions that the observed differences in systemic pharmacodynamic β2 responses at the conventional dose of two puffs twice daily would not have any clinically meaningful impact in terms of safety for patients switching from the reference to test formulation of FP/SM. As such we consider the two formulations to be clinically interchangeable at recommended doses.