Population pharmacokinetics of (R)-albuterol and (S)-albuterol in pediatric patients aged 4-11 years with asthma.
OBJECTIVE
To characterize the population pharmacokinetics (PK) of (R)- and (S)-albuterol in pediatric asthmatics using a model that supports a sparse blood sampling strategy.


METHODS
The data for this analysis were collected from patients enrolled in a randomized, double-blind, multicenter, placebo- and active-controlled study evaluating the safety and efficacy of levalbuterol in asthmatic children aged 4-11 years. Patients received either levalbuterol 0.31 mg, levalbuterol 0.63 mg, racemic albuterol 1.25 mg, or racemic albuterol 2.5 mg via nebulizer. Separate population pharmacokinetic models were developed for (R)- and (S)-albuterol using the NOMNEM((R)) computer program. Covariate models were developed to identify significant predictors of inter-patient variability.


RESULTS
A total of 995 samples and 262 patients were used for the (R)-albuterol population PK model while a total of 496 samples and 128 patients were used for the (S)-albuterol population PK model. The apparent clearance of (R)-albuterol was much more rapid than that of (S)-albuterol (approximately four-fold higher), and the apparent volume of distribution was much larger for (R)-albuterol (in part due to pre-systemic metabolism) than for (S)-albuterol (approximately four-fold higher).


CONCLUSIONS
In this study of pediatric patients, the models were able to demonstrate using two to four samples per patient that the apparent clearance and volume of distribution of (R)-albuterol were several fold higher than that of (S)-albuterol. The pharmacokinetics of (R)-albuterol were similar after administration of levalbuterol or racemic albuterol and were linear over the examined dose range (0.31-0.63 mg nebulized dose). The presence of (S)-albuterol did not significantly alter the pharmacokinetics of (R)-albuterol, suggesting that effects of (S)-albuterol may be due to the intrinsic pharmacology of this isomer.
Maier
Gary
G
Clinical Pharmacology, Sepracor Inc., 85 Waterford Drive, Marlborough, MA 01752-7010, USA. gmaier@sepracor.com
Rubino
Christopher
C
Hsu
Roger
R
Grasela
Thaddeus
T
Baumgartner
Rudolf A
RA
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D013237:Stereoisomerism; D014018:Tissue Distribution
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D000420:Albuterol