Prednisolone Pharmacokinetics in Severe Asthma
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

 1. to compare the effect of high dose prednisolone on clinical and physiological responses

 2. to determine the effect of long-term oral prednisolone therapy on corticosteroid
 responsiveness and prednisolone pharmacokinetics

 3. to measure the effect of high dose prednisolone for 14 days on p38 MAPK activity, GR
 translocation and activation of NF-kB

 4. 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
Asthma is a disease characterized by reversible airways obstruction, bronchial
 hyper-responsiveness, and chronic inflammation of the bronchial mucosal lining. Currently
 over 5 million people (6-8% of the population) in the UK are receiving treatment for asthma.
 Although most patients have mild-to-moderate asthma that is well-controlled by inhaled
 corticosteroids (ICS), in 5-10% of asthmatics, the disease is considered severe in that
 symptoms and control of asthma are largely unresponsive to treatment including systemic
 corticosteroids (CS). This subset of patients has greater morbidity and a disproportionate
 need for health care support in terms of use of drugs, admissions to hospital or use of
 emergency services, and time off work or school. Indeed, some severe asthma patients are also
 on oral CS in addition to ICS, and these patients are often described as being
 steroid-dependent since they need oral CS in addition to ICS to maintain their asthma
 control. Recent studies from our laboratory have shown that patients with severe asthma have
 relative corticosteroid resistance as measured by the responsiveness of peripheral blood
 mononuclear cells and alveolar macrophages to dexamethasone.

 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
Inclusion Criteria:

 -  for severe asthmatics:

 -  Physician diagnosis of asthma

 -  Aged 18 - 70

 -  Non-smokers or ex-smokers with less than 5 pack/year history

 -  Major characteristics (at least one of the following criteria)

 -  Treatment with continuous or near continuous (>50% of year) oral corticosteroids

 -  Requirement for treatment with high dose inhaled corticosteroids (ICS)

 -  Minor characteristics (at least 2 out of the following)

 1. Requirement for daily treatment with a controller medication in addition to
 ICS e.g. LABA, theophylline, leukotriene antagonist

 2. Asthma symptoms requiring SABA on a daily or near daily basis

 3. Persistent airways obstruction (FEV1 <80% predicted, diurnal PEF variation
 >20%)

 4. One or more emergency care visits for asthma per year

 5. 3 or more steroid "bursts" per year

 6. Prompt deterioration with ≤ 25% reduction in oral or ICS

 7. Near fatal asthma event in the past

 -  for moderately-severe asthma:

 -  Physician diagnosis of asthma

 -  Aged 18 - 70

 -  Non-smokers or ex-smokers with less than 5 pack/year history

 -  Less than 2 courses of prednisolone per year

 -  Taking up to 2000 mcg of inhaled corticosteroid (BDP equivalent) per day

 -  Stable asthma for at least 6 months prior to enrollment

 Exclusion Criteria:

 -  Current smokers, or less than 3 years since quitting smoking

 -  Less than 4 weeks from an exacerbation

 -  Diabetes

 -  Active peptic ulceration

 -  Previous history of psychiatric disturbances on high dose prednisolone

 -  On steroid-sparing agent or immunosuppressant such as azathioprine, methotrexate and
 ciclosporin

 -  Concomitant anti-IgE therapy

 -  Pregnancy