title: Clinical pharmacology of Cilomilast.
abstract: Chronic obstructive pulmonary disease (COPD) is a multicomponent, chronic inflammatory disease of the lungs with systemic complications. The majority of the inflammation occurs in the peripheral airways and lung parenchyma. It is a progressive disease, leading to disability and eventual death, despite conventional therapy. Inflammatory activity can be reduced by increasing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) through inhibition of phosphodiesterase (PDE) IV, the principal PDE isoenzyme within pro-inflammatory cells, including eosinophils, mast cells, macrophages, lymphocytes, neutrophils and epithelial cells. PDE IV inhibition also has other effects, including relaxation of airway smooth muscle, suppression of smooth muscle mitogenesis and modulation of excitatory activity in pulmonary nerves. Cilomilast is a systemically available, second-generation, selective PDE IV inhibitor. It retains the therapeutic activity of the first-generation PDE IV inhibitors but lacks their profound emetic effect. Cilomilast is the first drug to demonstrate a reduction of tissue cells considered central to the ongoing inflammatory process (macrophages and CD8+ lymphocytes) in patients with stable COPD. Cilomilast is completely absorbed following oral administration and has negligible first-pass metabolism. It exhibits linear pharmacokinetics, with low between-subject variability. Cilomilast is highly protein bound (99.4%), but this binding is concentration-independent at clinically relevant doses, and it has a small volume of distribution at steady state (17L). Plasma clearance (approximately 2 L/h) is almost entirely metabolic, through multiple parallel pathways. Its terminal elimination half-life is approximately 6.5 hours and steady state is rapidly achieved with twice-daily administration. The most abundant metabolite, formed by the action of cytochrome P450 2C8, has <10% of the activity of the parent molecule. Cilomilast pharmacokinetics in COPD patients were consistent with those in healthy subjects. Smoking, age and ethnicity had no clinically relevant effects. Total plasma cilomilast pharmacokinetic parameters did not change significantly with renal or hepatic impairment, but concentrations of unbound cilomilast increased with declining renal or hepatic function. Cilomilast had no clinically relevant interactions with a range of drugs likely to be coadministered to patients with COPD, with the exception of erythromycin where concurrent administration with cilomilast was associated with an increased incidence of gastrointestinal adverse events, a pharmacodynamic interaction predicted by their secondary pharmacology. Nausea was the principal adverse reaction seen in healthy subjects taking cilomilast, but this was reduced by administration with food or by use of simple dose-escalation regimens. Cilomilast has not shown a propensity for any of the serious cardiac or neurological adverse effects associated with theophylline. Cilomilast exhibits favourable and predictable pharmacokinetics, has few clinically relevant drug-drug interactions and has demonstrated effects on measures of inflammation of potential benefit in the treatment of COPD. It is generally well tolerated and has not generated safety concerns in any clinical study.
authors.affiliation: Respiratory Clinical Pharmacology, GlaxoSmithKline Research and Development, Greenford, England. geoff.x.down@gsk.com
authors.forename: Geoff
authors.initials: G
authors.lastname: Down
authors.forename: Sarah
authors.initials: S
authors.lastname: Siederer
authors.forename: Sam
authors.initials: S
authors.lastname: Lim
authors.forename: Peter
authors.initials: P
authors.lastname: Daley-Yates
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids; D004347:Drug Interactions; D006801:Humans; D009570:Nitriles / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; C433247:Cilomilast