Mometason Furoate Levels
2001; Elsevier BV; Volume: 120; Issue: 3 Linguagem: Inglês
10.1378/chest.120.3.1034
ISSN1931-3543
Autores Tópico(s)Inhalation and Respiratory Drug Delivery
ResumoI read with interest the article of Affrime et al (December 2000),1Affrime LB Kosoglou T Thonoor M et al.Mometasone furoate has minimal effects on hypothalamic-pituitary-adrenal axis when delivered at high doses.Chest. 2000; : 1538-1546Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar 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.2Lipworth BJ Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis.Arch Intern Med. 1999; 159: 941-955Crossref PubMed Scopus (845) Google Scholar 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.3Wilson AM McFarlane LC Lipworth BJ Effects of intranasal corticosteroid on adrenal, bone and blood markers of systemic activity in allergic rhinitis.J Allergy Clin Immunol. 1998; 102: 598-604Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 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.4Affrime M Cuss F Padhi D et al.Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers.J Clin Pharmacol. 2000; 40: 1227-1236PubMed Google Scholar 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.5Olsson B Aerosol particle generation from dry-powder inhalers: can they equal pressurized metered dose inhalers?.J Aerosol Med. 1995; 8: S13-S19Crossref PubMed Scopus (72) Google Scholar 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. Mometason Furoate LevelsCHESTVol. 120Issue 3PreviewWe 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. Full-Text PDF
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