Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects

Objectives of this study were to compare the pharmacokinetics, pharmacodynamics and safety of single cumulative doses of active (R)-salbutamol given either as the single enantiomer or racemic mixture by inhalation to subjects with mild to moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized study where all subjects received either four doses of 1.25 mg of (R)-salbutamol or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic parameters were determined by noncompartmental analysis and model-fitting. Changes in FEV1, plasma potassium, plasma glucose, heart rate, and QTc interval were measured. The potassium and glucose data were fitted to indirect response pharmacodynamic models. The heart rate and QTc data were evaluated using data descriptors. No significant differences in pharmacokinetics of (R)-salbutamol given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/- 4.37 and 11.47 +/- 2.88 ng.h/ml. The t(max) of about 2 h reflected serial dosing rather than delayed absorption. The t(1/2) averaged about 3.5 h. The (S)-salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2) of about 5 h. The changes in FEV1 reached a plateau after an initial increase and did not return to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several pharmacological responses including FEV1 were also similar and there were no unique safety concerns with either treatment.