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Ninewells Hospital and Medical School Dundee, Scotland
Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Pulmonology, Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland; e-mail: b.j.lipworth{at}dundee.ac.uk
To the Editor:
I read with interest the article of Affrime et al (December 2000),1 which concluded that mometasone furoate dry-powder inhaler at a dosage of 800 µg bid represents the lower limit for consistently detectable systemic effects. This would appear to be rather economical with the truth, as it was clearly evident from Figure 3 that the dosage 400 µg bid resulted in significant suppression of the serum cortisol area under the curve (AUC) 24 h after 7 days (p < 0.01), 14 days (p < 0.05), and 21 days (p < 0.05) as compared to placebo at the same time points. This analysis was based on the actual mean cortisol values rather than the mean change from baseline cortisol values, and it is noticeable that the baseline values for AUC 24 h was appreciably lower for 800 µg bid as compared to either placebo or 400 µg bid, which makes interpretation of the analysis somewhat difficult. The finding of an nonsignificant suppression of cortisol AUC 24 h on day 28 with 400 µg bid is surely a spurious result given the obvious variability in the placebo values over the serial time points.
The finding of a nonsignificant effect of mometasone furoate dry-powder 400 µg bid on the 250-µg cosyntropin response is hardly surprising given the known insensitivity of this test as compared to using a more physiologic 0.5-µg or 1-µg cosyntropin dose, which is widely recognized to be more appropriate for dynamic evaluation of impaired adrenal reserve.2
It was also particularly interesting to note with mometasone dry-powder inhaler, either 400 µg or 800 µg bid, that steady-state plasma concentrations were not achieved until after 14 days. This finding would be in keeping with a large volume of distribution for mometasone furoate, as it would take a long time to equilibrate between the extravascular lipid-soluble systemic tissue compartment and the water-soluble intravascular blood compartment. This in turn points to a high degree of lipophilicity of mometasone furoate, which would preferentially partition into the more lipid-soluble systemic tissue compartment, resulting in a large volume of distribution. For example, at a dosage of 400 µg bid of mometasone furoate dry-powder inhaler, there was a 54% increase in plasma mometasone furoate AUC between day 7 and day 14. This reinforces the importance of treating for at least 14 days with mometasone furoate in order to ensure that steady-state plasma levels have been achieved, in order to detect systemic bioactivity with this drug. A good example of this was a study from our own laboratory in patients with seasonal allergic rhinitis, where 5 days of intranasal mometasone furoate, 200 µg/d, appeared to have no detectable effect on 24-h plasma or urinary cortisol profiles or on serum osteocalcin or peripheral blood eosinophil count.3 In the light of the pharmacokinetic data from Affrime et al, this was probably an erroneous finding, as plasma mometasone levels would not have reached anywhere near steady state, in contrast to budesonide and triamcinolone where steady state would have been attained.
The findings of Affrime et al, showing evidence of detectable adrenal suppression and plasma drug levels with mometasone furoate dry-powder inhaler, 400 µg bid, at steady state would appear to conflict with the previous claims from Schering-Plough that this inhaled formulation exhibits < 1% systemic bioavailability, a claim that was based on a single-dose pharmacokinetic study with 400-µg dry powder, where plasma levels were below the lower limit of quantification for the mometasone assay.4
From the pharmacokinetic data presented, it is evident that the lung deposition and bioavailability from the mometasone furoate pressurized metered-dose inhaler (pMDI) is approximately half that of the dry-powder inhaler device. For example, the plasma mometasone AUC after day 14 was 473 pg h/mL for dry powder, 400 µg bid, as compared to 183 pg h/mL for the same dose of pMDI, as assessed in similar types of asthmatic patients. The greater numerical degree of suppression with fluticasone pMDI than mometasone furoate pMDI at comparable doses is perhaps not surprising given the higher efficiency for drug delivery with the fluticasone propionate pMDI device. The respirable dose fraction with fluticasone propionate pMDI is approximately twofold greater than fluticasone propionate dry-powder inhaler.5 This suggests that the difference in lung deposition between mometasone furoate pMDI and fluticasone propionate pMDI would be about twofold. It is therefore likely that if fluticasone propionate and mometasone furoate were compared via their respective dry-powder inhalers, mometasone furoate would produce adrenal suppression to a greater degree than fluticasone propionate at steady state, as lung deposition of the mometasone dry powder would be twofold greater than the fluticasone dry powder.
References
Schering-Plough Research Institute Kenilworth, NJ
Correspondence to: Melton B. Affrime, PharmD, Clinical Pharmacology, Schering-Plough Research Institute, 2015 Galloping Hill Rd, K15–4, Kenilworth, NJ 07033
To the Editor:
We thank Dr. Lipworth for his insightful comments and would like to take the opportunity to respond. Each of the studies presented in the article prospectively defined the 24-h serum cortisol area under the curve (AUC) after 28 days of treatment compared to placebo as the primary end point. Dr. Lipworth considers the finding of no statistically significant difference in the cortisol AUC on day 28 between the 400-µg bid mometasone-treated subjects and placebo-treated subjects "spurious" because earlier time points were statistically significantly different from placebo. The p values presented in Figure 3 were not, however, corrected for multiplicity of comparison. If one compares four paired values, this approximately quadruples the chance that any one pairwise comparison will be significant at the 0.05 level. Applying a Bonferroni correction for multiple comparisons,1 the p value needed for statistical significance falls to approximately 0.013. Thus, there was no statistically significant difference between the patients receiving placebo and patients receiving mometasone, 400 µg bid, at day 14, day 21, or day 28. The day 7 value remains statistically significantly different from placebo. This confirms that there is no consistent evidence of adrenal suppression after 28 days of administration of mometasone, 400 µg bid, to subjects with mild-to-moderate asthma.
The 250-µg cosyntropin test is a widely accepted method for safely assessing adrenal reserve. The low-dose cosyntropin test is claimed by some, including Dr. Lipworth, to be "more physiologic" and much more sensitive than the standard-dose cosyntropin test. The differences in the results of these two tests are much more subtle than Dr. Lipworth claims. While some authors have advocated the use of a low-dose test, it is not widely accepted for a variety of methodologic reasons.2 3 When compared to the "gold standard," a properly performed insulin tolerance test, the Pearson correlation coefficient between the peak cortisol response of the insulin tolerance test (ITT) population and the standard cosyntropin test was r2 of 0.89, while the correlation between the nonstandard, low-dose cosyntropin test and the ITT population was r2 of 0.91 to 0.930.4 Furthermore, the correlation coefficient between the responses 30 min after low-dose cosyntropin and high-dose cosyntropin treatments in patients with pituitary disease was r = 0.94,5 suggesting that the low-dose test was no more sensitive than the high-dose test.
While there appears to be an increase in plasma concentrations of mometasone between week 1 and week 2, there is high intersubject variability in the mean pharmacokinetic parameters as demonstrated by the large coefficients of variation observed in the parameters. Rather than this being due to an alteration in volume of distribution as suggested by Dr. Lipworth, this likely represents greater pulmonary absorption of mometasone due to decreased pulmonary inflammation and improved pulmonary deposition.
We have confirmed and extended the work Dr. Lipworth has performed in his laboratory. A study6 of the effect of 42 days of intranasal mometasone administered to subjects with allergic rhinitis showed no effect of 400 µg/d of mometasone nasal spray on 24-h cortisol AUC or 24-h urine cortisol excretion.
Finally, it was not our contention to compare "equivalent" doses of mometasone and fluticasone. Rather, the study presented in Figure 4 used the maximal labeled dose of fluticasone, 880 µg bid, and compared this to the highest approved dose of mometasone, 400 µg bid, and twice the maximal approved dose of mometasone. As can be seen from these data, there was a marked difference between the cortisol 24-h AUC seen at the highest labeled dose of fluticasone and doses one and two times the highest labeled dose of mometasone. In summary, we stand by the conclusions of our study.
References
This article has been cited by other articles:
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  H. Derendorf, R. Nave, A. Drollmann, F. Cerasoli, and W. Wurst Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur. Respir. J., November 1, 2006; 28(5): 1042 - 1050. [Abstract] [Full Text] [PDF]
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 T. C. Fardon, D. K. C. Lee, K. Haggart, L. C. McFarlane, and B. J. Lipworth Adrenal Suppression with Dry Powder Formulations of Fluticasone Propionate and Mometasone Furoate Am. J. Respir. Crit. Care Med., November 1, 2004; 170(9): 960 - 966. [Abstract] [Full Text] [PDF]
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 F. Caballero-Fonseca, M. Sanchez-Borges, and G. R.G. Todd Adrenal Suppression Related to Inhaled Corticosteroids Revisited Chest, September 1, 2002; 122(3): 1103 - 1104. [Full Text] [PDF]
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