Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

Edsbäcker, Staffan; Wollmer, Per; Selroos, Olof; Borgström, Lars; Olsson, Bo; Ingelf, Jarl

doi:10.1016/j.pupt.2007.08.005

Cited by 59 publications

(54 citation statements)

References 69 publications

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“…Likewise, 24-h urinary cortisol excretion (adjusted for creatinine) was lower with FP than with placebo treatment. Substantial suppression of adrenal function after inhalation of FP has been previously reported in healthy volunteers [19] and asthmatic patients [14,[20][21][22]. The presently observed degree of adrenal suppression with FP 1,000 mg?day -1 is somewhat smaller than the 29-34% suppression reported previously [14,17,20], possibly because it was given on top of a low maintenance dose of inhaled CIC.…”

Section: Discussioncontrasting

confidence: 48%

“…Several trials have shown that doses f1,280 mg?day -1 of CIC do not produce clinically relevant HPA-axis suppression in both healthy volunteers and asthma patients [13][14][15][16][17][18]. Fluticasone propionate (FP) is an established ICS, which, however, has been associated with pronounced suppression of HPA-axis function in healthy volunteers [19] and, to a lesser extent, in asthma patients [14,15,[20][21][22]. Thus, the current study was designed to assess the safety of CIC and FP in patients with persistent asthma chronically treated with ICS.…”

mentioning

confidence: 99%

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Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma

Derom

Louis

Tiesler³

et al. 2009

European Respiratory Journal

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We compared the systemic and clinical effects of ciclesonide (CIC) and fluticasone propionate (FP) administered, in addition to CIC 160 mg?day -1 and salmeterol 50 mg twice daily, in 32 patients with persistent asthma using a randomised double-blind, placebo-controlled, doubledummy, five-period crossover design. All patients exhibited a provocative concentration leading to a 20% decrease in forced expiratory volume in 1 s (PC20) methacholine ,8 mg?mL -1 and a PC20 adenosine ,60 mg?mL -1 . Primary outcome was 24-h serum cortisol suppression after 7 days. Secondary outcomes were changes in PC20 methacholine and adenosine after 9 days.FP 500 mg?day : -38.8 (95% CI -75.7--1.9) nmol?L -1 ). Compared with placebo, the increase in PC20 adenosine after the four treatments was small, but significant. Greater improvements in PC20 adenosine were seen with FP 500 mg?day . For a similar decrease in hyperresponsiveness, cortisol secretion was suppressed significantly with moderate-to-high doses of fluticasone propionate, but not with ciclesonide.

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Section: Discussioncontrasting

confidence: 48%

mentioning

confidence: 99%

Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma

Derom

Louis

Tiesler³

et al. 2009

European Respiratory Journal

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“…In addition, particles deposited in the central conducting airways are cleared faster than particles deposited in the peripheral conducting airways, as mucociliary clearance increases from peripheral (small bronchi) to central conducting airways (trachea). Mucociliary clearance clears particles in these airways to the mouth-throat region, where drug may subsequently be swallowed and absorbed from the GI tract (24). These pulmonary clearance processes are more relevant for undissolved drug particles (25), i.e., slowly dissolving drug formulations will be more susceptible than rapidly dissolving formulations or solutions.…”

Section: Pulmonary Mucociliary/macrophage Clearancementioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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Abstract. During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

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“…Systemic availability of slowly dissolving drugs such as fluticasone propionate decrease with decreased lung function, as more drug is delivered centrally (9). FDA recommends PK studies be performed in healthy volunteers.…”

Section: Subject Population/study Designmentioning

confidence: 99%

Pharmacokinetics of Orally Inhaled Drug Products

Hochhaus

Horhota

Hendeles

et al. 2015

AAPS J

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Abstract. The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.

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Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

Cited by 59 publications

References 69 publications

Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma

Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Pharmacokinetics of Orally Inhaled Drug Products

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