title: Characterizing systemic exposure of inhaled drugs: application to the long-acting β2-agonist PF-00610355.
abstract: OBJECTIVE
  PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic exposure, across trials and patient populations.
  
  
  METHODS
  A total of 6,107 samples of PF-00610355 plasma concentration, collected in 264 subjects from eight studies in healthy volunteers, asthma, and COPD patients, were analyzed using non-linear mixed-effects models. Model-based mean (95 % CI) exposure profiles for a range of PF-00610355 doses in COPD patients were simulated.
  
  
  RESULTS
  PF-00610355 exposure profiles were described by a three-compartment disposition model with first-order absorption through a transit compartment. Patient status, inhalation device, and demographic factors were found to influence systemic drug exposure. Relative fine particle dose had a minor effect, whereas no effect of baseline lung function on the systemic exposure was found. An implicit method to address pharmacokinetic variability between occasions of drug intake yielded similar results as the established explicit method, yet in a much more efficient way.
  
  
  CONCLUSIONS
  The estimated systemic pre-dose and maximum PF-00610355 plasma concentration was 23 and 38 % in COPD patients compared to healthy volunteers, respectively. The analysis illustrated the value of an integrated pharmacokinetic analysis to address specific challenges in the clinical development of long-/ultra-long-acting β2-agonists and inhaled compounds in general, both in relation to selecting a safe starting dose in patients, but also in understanding exposure and systemic safety information across different patient populations and different inhalation devices/formulations.
authors.affiliation: Quantitative Solutions BV, Breda, The Netherlands.
authors.forename: Paul Matthias
authors.initials: PM
authors.lastname: Diderichsen
authors.forename: Eugène
authors.initials: E
authors.lastname: Cox
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Adriaan
authors.initials: A
authors.lastname: Cleton
authors.forename: Jakob
authors.initials: J
authors.lastname: Ribbing
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D001249:Asthma / Q000097:blood / Q000188:drug therapy; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists