Prednisolone Pharmacokinetics in Severe Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 4

Summary: 
      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
    

Detailed description: 
      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
    

Intervention name(s): prednisolone
Intervention type(s): Drug
Intervention description(s): 40mg of prednisolone once a day for 14 days
Intervention MeSH terms: Prednisolone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: severe asthma; prednisolone pharmacokinetics; anti-inflammatory effects