Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.