The protective efficacy of inhaled, oral and intravenous nedocromil sodium against adenosine-5′-monophosphate-induced bronchoconstriction in asthmatic volunteers

Abstract

We have investigated the pharmacokinetics and pharmacodynamics of nedocromil sodium administered by inhalation (4mg), by mouth (80 mg) and by intravenous infusion (6μg/kg) against adenosine-5′-monophosphate (AMP) induced bronchoconstriction in 9 mildly asthmatic subjects. Their mean baseline FEV 1 was 83.8% of the predicted value, geometric mean (GM) PC 20 FEV 1 histamine 0.33 mg/ml (range 0.03–4.0), and GM PC 50 baseline sGaw AMP 4.37 mg/ml (range 0.158–26.38). Blood collected at intervals for up to 4 h after drug administration was assayed for nedocromil sodium by radioimmunoassay, to derive the maximal drug concentration (Cmax), concentration at time of AMP challenge (Cchall), area under the plasma concentration-time curve (AUC), and the mean residence time (MRT). Airways responsiveness to inhaled AMP was assessed before and after administration of nedocromil sodium by each of the three routes of administration, and the protective efficacy was expressed as the concentration ratio (CR). AMP challenge was carried out 60 min after inhaled nedocromil sodium, 120 min after drug ingestion and 75 min after the start of the intravenous infusion. The GM PC 50 sGaw AMP determined after inhaled, oral and intravenous nedocromil sodium was 28.84,7.24 and 7.94 mg/ml respectively. For the group as a whole, nedocromil sodium by the oral or intravenous routes produced little overall protection against AMP (CR increasing by 0.75 and 0.88 doubling dilutions respectively). However, with inhaled drug, the concentration response curve with AMP was displaced to the right achieving an increased CR of 2.71 doubling dilutions. No relationship could be established between baseline FEV 1, and AUC, Cmax or Cchall, or between these indices and the protective efficacy for the drug. Overall, there were significant correlations for PC 20 FEV 1 histamine and PC 50 sGaw AMP and the protective efficacy of all three routes of nedocromil sodium. The mean residence time for inhaled nedocromil sodium (129 ± 12 min) was significantly longer than for IV nedocromil sodium (48 ± 6 min) (p<0.001). Thus nedocromil sodium given by inhalation is absorbed slowly from the lungs and is most efficacious against provocation when administered by the inhaled route.