Pharmacokinetics of andolast after administration of single escalating doses by inhalation in mild asthmatic patients

The pharmacokinetics of andolast, a new tetrazolyl-benzamido derivative with antiallergic, antiinflammatory, mucosal protective and antisecretive activities, have been investigated in patients suffering from mild asthma (FEV1 greater than or equal to 70% of predicted) in Whom obstruction Was reversible (FEV1 increase greater than or equal to 15% of initial) after the administration of 0.2 mg of salbutamol by inhalation. Twelve out-patients (seven males and five females) were enrolled in the present study and were treated with a single dose of andolast of 2, 4 and 8 mg by inhalation using the MIAT Monohaler (R) device according to a randomised crossover design. Plasma samples were collected before drug administration and up to 540 min after dosing. Andolast plasma concentrations Were determined using a validated LC-MS/MS method with a limit of quantitation of 0.2 ng ml(-1). Pharmacokinetic analysis was carried out using standard non-compartmental methods. In addition, andolast safety and tolerability were evaluated by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence of adverse events throughout the study period. Andolast was absorbed after inhalation and was available to the systemic circulation. The mean peak plasma concentrations were 6.3, 10.9 and 30.5 ng ml(-1) at the three doses, respectively, and occurred at 30, 52.5 and 30 min (median t(max)). The mean AUC(t) values were 1852, 2889 and 7677 ng min ml(-1). The apparent plasma clearance (CL/F) and volume of distribution (V-z/F) were, respectively, 1168 ml min(-1) and 4301 at the dose of 2 mg, 1143 ml min(-1) and 4681 at the dose of 4 mg, and 1141 ml min(-1) and 4861 at the dose of 8 mg. The apparent elimination half-life averaged 4.5, 5.0 and 4.6 h at the three doses, respectively. Even though the small number of subjects participating in the present study reduced the power of the statistical test, there was no statistically significant evidence of non-proportionality for all the andolast pharmacokinetic parameters calculated at the three doses. Thus, the data obtained as a whole suggest that andolast pharmacokinetics are dose-independent in the dose range investigated. Finally, the safety and tolerabilty of the drug administered to mild asthmatic patients was good up to the maximum investigated dose of 8 mg. Copyright (C) 2001 John Wiley & Sons, Ltd.