This study compared the effect of MF-DPI on the HPA axis with that of another commonly used ICS, BDP, in subjects with asthma. The results demonstrate that a similar magnitude of HPA-axis suppression occurred with BDP via HFA and CFC MDI, despite the differences in BDP doses: 200 ^g bid vs 400 ^g bid. This confirms previous findings by Jackson and Lipworth- indicating greater systemic bioavailability and enhanced cortisol suppression with the HFA formulation of BDP vs the CFC formulation. The median percentage reduction in the serum cortisol concentrations AUC0-24 of 23 to 24% with BDP was significantly greater than the 9% reduction seen with MF-DPI treatment. This low magnitude of cortisol secretory suppression seen with MF-DPI is in keeping with a previous 28-day study in subjects with mild-to-moderate asthma. In that study, MF-DPI at doses from 200 ^g bid to 1,200 ^g qd had no impact on dynamic cortisol secretion in response to low-dose cosyntropin, while the mean serum cortisol concentrations AUC0-24h was in the range of 82 to 107% of placebo.
The minor effect of MF-DPI treatment on serum cortisol concentrations AUC0-24h compared with BDP in the current study was reflected in the results of the 24-h UFC excretion. The mean decrease in 24-h UFC excretion of 9.6% ( — 8.2 nmol/L/24 h) with MF-DPI was lower than the decreases seen with HFA-BDP (34.3%; — 27.9 nmol/L/24 h; p = 0.047) and CFC-BDP (33.4%; — 18.0 nmol/ L/24 h; p = 0.073). The difference between the MF-DPI and BDP groups was maintained in the subpopulation with validated full 24-h urine samples (MF-DPI, — 9.6% [— 5.9 nmol/L/24 h]; HFA-BDP, — 43.1% [— 34.8 nmol/L/24 h]; and CFC-BDP, — 30.0% [— 19.1 nmol/L/24 h]). Subjects in the MF-DPI group had greater improvements from baseline in PEF measured morning (35 L/min) and evening (41 L/min), compared with BDP (morning, 20 to 21 L/min; evening, 17 L/min; p = not significant).
Various methodologies have been used to measure the impact of ICSs on the HPA axis, but not all are sufficiently sensitive to detect suppression of HPA-axis activity. Appropriate test selection is particularly important when attempting to compare the effects of ICSs on the HPA axis. Basal HPA-axis function is best assessed using timed serum or plasma cortisol sampling, with 12-h overnight (8 pm to 8 am) and 24-h periods having been validated. Spot morning cortisol assessments are now recognized as being insensitive markers of HPA-axis suppression, and may miss as many as 15% of cases of documented hypoadrenalism. The results of the current study reinforce these doubts regarding the sensitivity of spot morning cortisol assessments. There were marked variabilities in the differences between baseline and posttreatment from 6 to 10 am in all treatment groups (Fig 1), indicating that a single measurement is not reliable to capture accurately the relative effects of various ICSs on cortisol secretion. The use of timed UFC excretion to assess the impact of ICSs on the HPA axis has been reported to suffer from intrastudy variability, and appropriate assays must be used. Others- have found, however, that timed UFC collections are a sensitive measure of HPA suppression with ICSs, and we found that 24-h UFC excretion mirrored the results of serum cortisol concentration AUC0-24h closely, particularly when total timed urine collections are confirmed as comparable. For dynamic testing of adrenal reserve, the low-dose cosyntropin test is preferred to the previous high-dose test, as it is more sensitive, returns fewer false results, and correlates better with the insulin-tolerance test. We did not test adrenal reserve in this study, but, as noted above, previous work has shown that mometasone furoate had no impact on the low-dose cosyntropin test at doses of 400 to 1,200 ^g/d.
The lower impact of MF-DPI on HPA-axis function as compared to HFA-BDP and CFC-BDP may be attributable to the relatively low systemic bioavailability of MF-DPI and its delivery by the dry powder inhaler device. Mometasone furoate has a high glucocorticoid receptor affinity, which is 22 times the relative receptor affinity of dexamethasone. The bioavailability of inhaled mometasone furoate has been estimated to be of the order of only 1%, which is largely determined by extensive first-pass metabolism of any swallowed drug. Furthermore, as dry powder inhaler delivery of ICSs results in higher lung deposition than delivery via CFC and HFA propellants, it appears that subsequent entry of inhaled MF-DPI from the lung into the systemic circulation does not occur to a significant degree, perhaps due to elimination by hepatic metabolism. On a separate point, it has been shown that the systemic bioavailability of an ICS may depend on the severity of lung compromise, with asthmatic patients having lower systemic exposure to inhaled fluticasone propionate than healthy volunteers. This underlines the importance of performing pharmacokinetic studies of ICSs at therapeutic doses in patients with asthma—as we did in this study—rather than simply extrapolating data from a healthy population.
In conclusion, this study demonstrates that in subjects with mild asthma, 14 days of treatment with MF-DPI 400 ^g qd has a significantly lower effect on HPA-axis function as assessed by serum cortisol concentrations AUC0-24h and UFC, as compared with HFA-BDP (200 ^g bid) and CFC-BDP (400 bid). Further studies would be useful to determine whether this benefit of MF-DPI over HFA-BDP and CFC-BDP in terms of HPA-axis function endures during long-term treatment of asthma in the clinical setting.