Population pharmacodynamic model of bronchodilator response to inhaled albuterol in children and adults with asthma.
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.
Blake
Kathryn
K
Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, Jacksonville, FL. Electronic address: kblake@nemours.org.
Madabushi
Rajanikanth
R
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL.
Derendorf
Hartmut
H
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL.
Lima
John
J
Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, Jacksonville, FL.
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
D001993:Bronchodilator Agents; D000420:Albuterol