Prednisolone Pharmacokinetics in Severe Asthma
The purpose of the study is to evaluate whether severe asthmatic subjects have abnormal prednisolone absorption, and how this might affect the anti-inflammatory effects of prednisolone.
The aims of the study are
- to compare the effect of high dose prednisolone on clinical and physiological responses
- to determine the effect of long-term oral prednisolone therapy on corticosteroid responsiveness and prednisolone pharmacokinetics
- to measure the effect of high dose prednisolone for 14 days on p38 MAPK activity, GR translocation and activation of NF-kB
- to validate an easier method of measuring corticosteroid insensitivity using whole blood, and a spot prednisolone serum level as a measure of adherence to prednisolone therapy
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||The Pharmacokinetics and Anti-inflammatory Effects of Prednisolone in Severe Asthma|
- serum prednisolone levels over 24 hours [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- change in FEV1 24 hours post prednisolone [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- changes in eNO, sputum eosinophils and inflammatory mediators over 24 hours [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- difference between day 1 and day 14 in serum prednisolone levels [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- difference in FEV1 between day 1 and day 14 [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- difference in inflammatory markers between day 1 and day 14 [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- changes in asthma control symptoms before and after treatment [ Time Frame: 14 days ] [ Designated as safety issue: No ]
|Study Start Date:||June 2011|
|Study Completion Date:||January 2013|
|Primary Completion Date:||January 2013 (Final data collection date for primary outcome measure)|
|Experimental: Severe Asthma||
40mg of prednisolone once a day for 14 days
Hide Detailed Description
In asthma, corticosteroid- resistance (CSR) has usually been defined on the basis of changes in baseline FEV1 (forced expiratory volume in one second) after a 14-day course of oral prednisolone of 40mg/day; an increase of less than 15% of the baseline measurement, while demonstrating a greater than 15% improvements in FEV1 following inhaled β2-agonist, has been used. Patients who showed an improvement in FEV1 of 30% or more were considered as corticosteroid-sensitive (CSS). The arbitrary cut-off response of <15% response was chosen empirically without the knowledge of the distribution of responses to oral or inhaled CS. CSR asthmatics are not completely resistant to the effects of corticosteroids, as stopping corticosteroid therapy leads to a clinical deterioration. It is not known at present whether the reduced corticosteroid responsiveness seen in severe asthma is genetically-determined or acquired, or both. Patient with CSR as defined above are not necessarily patients with severe asthma. The response of patients with severe asthma to a formal trial of oral prednisolone on lung function or inflammatory parameters has not been studied in detail. For example, it is not known whether the absorption of oral prednisolone which is commonly used to treat exacerbations of asthma is normal in patients with severe asthma. Pharmacokinetic studies have been reported in normal subjects and mild-moderate asthma, and also in CS-resistant asthmatics, and 'normal' pharmacokinetics has been reported in the latter groups. However, we need to exclude this as a potential course of relative CS-resistance in severe asthma.
Corticosteroids are known to exert anti-inflammatory effects as assessed in bronchial biopsies, which is the basis of its beneficial effects in asthma. These effects can also be assessed non-invasively using measurements of exhaled nitric oxide (eNO) or induced sputum eosinophil counts. The effect of a prednisolone trial on these measurements has not been performed. We have previously shown the value of measuring IL-8 release from whole blood as a marker of the inflammatory response. Serum IL-8 and TNF-α have been found to be higher in severe asthmatics than in the mild-moderate asthmatics. Therefore, we propose to study the response of patients with severe asthma to oral prednisolone, looking at drug levels and their anti-inflammatory effects. Anecdotally, we have found that many of our severe asthmatic patients have low prednisolone levels, even though they have been compliant with their medication. Spot levels of prednisolone (one-off measurements of blood levels) are used to check compliance. The effect of continuous oral therapy on prednisolone levels and its suppression of inflammation is unknown. It has been previously postulated that such therapy may lead to a reduction in the effectiveness of corticosteroids as an anti-inflammatory agent. Therefore, we propose to study two groups of patients with severe asthma, those on ICS alone and those on ICS plus a maintenance dose of prednisolone ranging 5-20 mg/day; the control group would be moderately-severe asthmatics who are well controlled on ICS.
The patients will be given a fourteen-day course of daily 40mg of prednisolone (non enteric-coated tablets). Subjects will attend the Asthma Lab at the Royal Brompton Hospital for screening. They will keep peak expiratory flow rate (PEFR) and symptom diary cards for 2 weeks prior to and during the two week course of prednisolone. Patients already on prednisolone will have the maintenance dose increased to 40mg. There will be 5 study visits.
On Visits 2 and 4, patients will be fasting overnight and will have the blood tests at time 0 hours. They will then take the prednisolone with or after having their breakfast. Sputum and blood samples will be taken, spirometry and exhaled nitric oxide measured at various time intervals as specified in the protocol. Visits 3 and 5 will be 24 hours post 1st and last prednisolone dose
Please refer to this study by its ClinicalTrials.gov identifier: NCT00662298
|Asthma Laboratory, Royal Brompton Hospital|
|London, United Kingdom, SW3 6LY|
|Principal Investigator:||Kian F Chung||Imperial College London|