Effect of Pioglitazone on Inflammation in Cystic Fibrosis

Progressive loss of lung function due to chronic infection and inflammation is the primary cause of morbidity and mortality in patients with CF. Current therapies directed at treatment of chronic P. aeruginosa infection (e.g. aerosolized tobramycin, azithromycin) provide short-term improvement in pulmonary function; however, persistence of the infection/inflammation causes the inevitable loss of lung function. PPARgamma is a nuclear transcription factor which is known to reduce activation of NFKB, a central mediator of airway inflammation in CF. Recent studies demonstrate that PPARgamma expression is reduced in patients with CF and may offer a potential therapeutic target to combat airway inflammation in CF. Pioglitazone is a thiazolidinedione whose principal pharmacological target it PPARgamma. The purpose of this pilot study is to determine the pharmacokinetics/pharmacodynamics of pioglitazone and effect on reducing airway inflammation in cystic fibrosis.

Inclusion criteria

• Age greater than 18 years
• Clinically stable (FEV1 within 10% of baseline)
• FEV1 > 40% predicted

Exclusion criteria

• History of hypoglycemic events
• Hepatic disease (AST, ALT > 2.5x ULN)
• Renal disease (GFR < 60 ml/min - 1.73m2)
• Currently receiving beta-blocker, oral corticosteroids, statin, angiotensin receptor blocker, trimethoprim-sulfamethoxazole, gemfibrozil, or rifampin therapies.
• Allergy to thiazolidinediones
• Pregnancy or attempting to conceive, breast feeding
• Hematocrit < 30
• Congestive heart failure
• Pulmonary hypertension