title: Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease.
abstract: Cilomilast (Ariflo, SB-207499) is an orally-active, second generation phosphodiesterase (PDE) inhibitor that may be effective in the treatment of asthma and chronic obstructive pulmonary disease (COPD). It has high selectivity for the cyclic AMP-specific, or PDE4, isoenzyme that predominates in pro-inflammatory and immune cells and is ten-fold more selective for PDE4D than for PDE4A, B and C. In vitro, cilomilast suppresses the activity of many pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD and is highly active in animal models of these diseases. Cilomilast demonstrates a markedly improved side effect profile over the archetypal PDE4 inhibitor, rolipram, which has been attributed to its inability to discriminate between the high affinity rolipram binding site and the catalytic domain of the enzyme, and the fact that it is negatively charged which at physiological pH should limit its penetration in to the CNS. In humans cilomilast is rapidly absorbed after oral administration, providing dose-proportional systemic exposure up to 4 mg, completely bioavailable, has a half-life of approximately 7 h and is subject to negligible first pass hepatic metabolism. Cilomilast is extensively metabolised with decyclopentylation, acyl glucuronidation and 3-hydroxylation of the cyclopentyl ring representing the principal routes. Most of the drug is excreted in the urine (approximately 90%) and faeces (6 - 7%) with unchanged cilomilast accounting for less than 1% of the administered dose. Cilomilast has been evaluated in Phase I, Phase II and Phase III trials and dose-response experiments have demonstrated a clinically significant increase in lung function and a perceived improvement in quality of life in patients with COPD. Trials of cilomilast in asthma have been less impressive although a trend towards improved lung function has been reported. Cilomilast is safe and well-tolerated at doses up to 15 mg in both short- and long-term dosing trials with a low incidence of adverse effects. No evidence for drug-drug interactions with commonly prescribed medications for COPD and asthma such as digoxin, corticosteroids, salbutamol, theophylline or warfarin has been found. Moreover, the pharmacokinetics of cilomilast are essentially the same in smokers and non-smokers, indicating that no dose adjustments of cilomilast will be required in patients with COPD. Thus, cilomilast displays a promising clinical profile in the treatment of inflammatory airway diseases, in particular COPD and the results of further Phase III trials are awaited with interest.
authors.affiliation: Thoracic Medicine, National Heart & Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. m.giembycz@ic.ac.uk
authors.forename: M A
authors.initials: MA
authors.lastname: Giembycz
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004347:Drug Interactions; D004361:Drug Tolerance; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D001993:Bronchodilator Agents; D002250:Carbon Radioisotopes; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; C517376:PDE4D protein, human