title: Population pharmacodynamic model of bronchodilator response to inhaled albuterol in children and adults with asthma.
abstract: BACKGROUND
  Because interpatient variability in bronchodilation from inhaled albuterol is large and clinically important, we characterized the albuterol dose/response relationship by pharmacodynamic modeling and quantified variability.
  
  
  METHODS
  Eighty-one patients with asthma (24% African American [AA]; 8 to 65 years old; baseline FEV1, 40 to 80% of predicted) received 180 microg of albuterol from a metered-dose inhaler (MDI), and then 90 microg every 15 min until maximum improvement or 540 microg was administered; all then received 2.5 mg of nebulized albuterol. FEV1 was measured 15 min after each dose. The population cumulative dose/response data were fitted with a sigmoid maximum effect of albuterol (Emax) [maximum percentage of predicted FEV1 effect] model by nonlinear mixed-effects modeling. The influence of covariates on maximum percentage of predicted FEV1 reached after albuterol administration (Rmax) and cumulative dose of albuterol required to bring about 50% of maximum effect of albuterol (ED50) and differences between AA and white patients were explored.
  
  
  RESULTS
  ED50 was 141 microg, and Emax was 24.0%. Coefficients of variation for ED50 and Emax were 40% and 56%, respectively. Ethnicity was a statistically significant covariate (p < 0.05). AA and white patients reached 82.4% and 91.9% of predicted FEV1, respectively (p = 0.0004); and absolute improvement in percentage of predicted FEV1 was 16.6% in AA patients vs 26.7% in white patients (p < 0.0003). There were no baseline characteristic differences between AA and white patients. Nebulized albuterol increased FEV1 > or = 200 mL in 21% of participants. Heart rate and BP were unchanged from baseline after maximal albuterol doses.
  
  
  CONCLUSIONS
  Our model predicts that 180 microg of albuterol by MDI produces a 14.4% increase in percentage of predicted FEV1 over baseline (11.7% in AA patients, and 17.5% in white patients). Emax varies widely between asthmatic patients. AA patients are less responsive to maximal doses of inhaled albuterol than white patients.
authors.affiliation: Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, Jacksonville, FL. Electronic address: kblake@nemours.org.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Blake
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL.
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Madabushi
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.affiliation: Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, Jacksonville, FL.
authors.forename: John
authors.initials: J
authors.lastname: Lima
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D011159:Population Surveillance / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D000420:Albuterol