1995 Volume 26 Issue 4 Pages 845-856
The safety, tolerability and pharmacokinetics of DO-309 (doxofylline: DOX), a new anti-asthmatic agent, were investigated in 30 healthy male volunteers after single oral administration of 200 mg, 400 mg, 800 mg, 1, 000 mg and 1, 200 mg DO-309 in a doseescalating fashion. During the study, the effect of food intake on the kinetics of DO-309 was determined in 6 subjects after a 400 mg single dose during fasting and at 30 minutes after a meal with a cross-over design. The effect of smoking was also evaluated in 8 subjects (4 smokers and 4 non-smokers) given 400 mg DO-309 during fasting.
All subjects completed the study without any adverse effects. No apparent changes in blood pressure, pulse rate, body temperature or clinical laboratory data were observed in any subject. In the dose-escalating study, the absorption of DOX was rapid (tmax: 0.60 -0.86 h) following administration of DO-309. Non-linear pharmacokinetics were observed for t1/2, Cmax and AUC of DOX with a dose-dependent increase after each dose. A dose-related increase, however was observed for Cmax and AUC of the main metabolites of DOX, theophylline-7-acetic acid (T-7 A) and hydroxyethyl theophylline (OH-ET). Total urinary excretion of DO-309 for 48 hours was around 70-80% of the dose adminis tered in each step.T-7 A was a major component of the total excreted into urine ; a very slight amount of DOX was found. Food intake slightly delayed tmax and decreased Cmax of DOX but did not change t1/2 and AUC of the drug. Regarding the influence of smoking on the pharmacokinetics of DO-309, AUC and Cmax of DOX were remarkably decreased in smokers, while no change was observed for those of the metabolites.
Single oral administration of DO-309 was well tolerated within the dose range used in this study and the results support the feasibility of repeat administration of DO-309 in healthy male volunteers.
