A Study to Assess the Effects of Fluticasone Furoate and GW642444M Combination in Healthy Subjects and in Subjects With Mild, Moderate or Severe Hepatic Impairment.
Condition: Asthma
MeSH terms: Liver Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      In relation to their severity, hepatic diseases can significantly modify drug absorption and
      disposition and consequently can interfere with drug efficacy and/or produce toxicity. The
      purpose of this study will be to aid in deciding whether a dose adjustment is required in
      subjects with hepatic impairment and in estimating any such adjustments.
    

Detailed description: 
      In relation to their severity, hepatic diseases can significantly modify drug absorption and
      disposition and consequently can interfere with drug efficacy and/or produce toxicity.
      Pathological modifications of liver structure or functionality might result in complex
      modifications of various factors including liver blood flow, hypoalbuminaemia, indirectly
      affect renal function and reduce the hepatic drug metabolizing capability including the
      microsomal oxidase system [Howden, 1989].

      Although FF/GW642444M is delivered directly to the site of action, i.e. the lungs, a large
      portion of the administered dose is swallowed. For both FF and GW642444 any drug absorbed
      from the GI tract undergoes first pass metabolism via CYP3A4. In addition, drug absorbed into
      the systemic circulation is metabolised in the liver and removed by biliary clearance. Hence,
      there is a possibility that when used by patients with impaired liver function the
      pharmacokinetics of inhaled FF and/or GW642444 may be changed due to reduced first pass
      metabolism and/or reduced clearance. The results of this study will aid in deciding whether a
      dose adjustment is justified and in estimating any such adjustments in patients with impaired
      hepatic function.

      This is an open-label, non-randomized study which will assess the pharmacokinetics and safety
      of inhaled FF 200mcg/GW642444M 25mcg in subjects with hepatic impairment following 7 days
      once daily dosing. Subjects with mild, moderate and severe hepatic impairment (as defined by
      a Child-Pugh score of 5-15) will be recruited along with healthy control subjects matched to
      the moderate subjects (matched on gender, ethnicity, body mass index +/-15%, age +/-5 years).

      Approximately thirty-six subjects will be recruited: 9 subjects for each severity and 9
      matched healthy subjects. All subjects are scheduled to receive FF 200mcg/GW642444M 25mcg
      once daily for 7 days. The dose for subjects with severe hepatic impairment may be adjusted
      to FF 100mcg/GW642444M 12.5mcg after review of the PK and safety data from the moderate and
      healthy matched control subjects. The results of this study will aid in deciding whether a
      dose adjustment is required in subjects with hepatic impairment and in estimating any such
      adjustments.
    

Intervention name(s): Inhaled FF 200mcg/GW642444M 25mcg
Intervention type(s): Drug
Intervention description(s): All subjects are scheduled to receive FF 200mcg/GW642444M 25mcg once daily for 7 days. The dose for subjects with severe hepatic impairment may be adjusted to FF 100mcg/GW642444M 12.5mcg after review of the PK and safety data from the moderate and healthy matched control subjects.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: pharmacokinetics; hepatic impairment; heart rate; serum potassium; serum cortisol; GW642444M; Fluticasone furoate (GW685698)