Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease.

A long-term evaluation of the therapeutic efficacy and safety of oral almitrine bismesylate (AB) (50 mg twice daily) was made on 25 patients with COPD and moderate hypoxemia residing at an altitude of 1,500 m in a double-blind placebo-controlled study. Thirteen patients receiving AB (baseline PaO2, 54.3 +/- 4.9 mm Hg; mean +/- SD) and 12 patients receiving placebo (baseline PaO2, 53.0 +/- 4.1 mmHg) were periodically followed by arterial blood gas and other pulmonary function studies and plasma levels of AB. Eight patients receiving AB and nine patients receiving placebo were followed for 1 yr; all patients were followed for at least 90 days. AB administration resulted in an increase in PaO2 to 62.2 +/- 9.3 mm Hg (p less than 0.01) on Day 28. The increase was maintained until Day 360 (63.8 +/- 4.6 mm Hg; p less than 0.01). The mean plasma concentration of AB on Day 28 was approximately one-half that on Day 90 when the plasma level reached a near maximum. AB was associated with weight loss (five of 13 patients receiving AB lost more than 10% of their baseline body weight) and peripheral paresthesias of the lower extremities (three patients), both occurring at the peak plasma levels of the drug. We conclude that AB causes a long-term improvement in arterial oxygenation in hypoxemic patients with COPD residing at an altitude of 1,500 m. Our data suggest that lower doses of AB might produce the same effect on PaO2 with less adverse associated effects, and this should be tested in future studies.

Relative bioavailability of almitrine bismesylate in humans.

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0.5 per cent (w/v) oral reference solution of almitrine bismesylate in d,l malic acid. The U.S. manufactured formulations were 85.88 and 87.85 per cent of the calculated mean area under the individual concentration-time curve for almitrine bismesylate reference solution compared to 88.40 and 88.86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176.3 ng ml-1 and 180.1 ng ml-1 compared to 196.3 and 200.1 ng ml-1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3.22, 3.33, 3.06, and 3.26 h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222.8 ng ml-1 and a mean time to peak plasma concentration of 2.68 h. Analysis of variance and multiple range comparisons (p less than 0.05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.

One year administration of almitrine bismesylate (Vectarion) to chronic obstructive pulmonary disease patients: pharmacokinetic analysis.

A double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50 mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen-phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p less than 0.01) between test day 14 and test day 360 (243 +/- 213 per cent and 199 +/- 170 per cent for predose and 3h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half-life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500 ng ml-1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700 ng ml-1. Mean accumulation was estimated to be 4.21 +/- 1.98 at one year.

Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans.

A single-blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen-phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0.96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200 mg dose. The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38.9 +/- 11.8 to 286.2 +/- 99.1 ng ml-1 for the 25 and 200 mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2.4 +/- 0.5 h to 2.8 +/- 0.8 h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268.2 +/- 132.8 to 436.4 +/- 191.4 ml min-1 for doses 50 and 200mg, respectively.

Long-term effects of almitrine bismesylate on oxygenation during wakefulness and sleep in chronic obstructive pulmonary disease.

Hypoxemia in patients with chronic obstructive pulmonary disease (COPD) becomes more pronounced during sleep and can result in a number of serious consequences. Almitrine bismesylate is a peripheral chemoreceptor agonist that improves arterial oxygen tension (PaO2) in patients with COPD during wakefulness. Studies conducted for up to six months suggested the agonist may be useful in the management of nocturnal hypoxemia. In this double-blind, parallel, placebo-controlled study, patients with COPD received 50 mg of almitrine bismesylate (n = 9) or placebo (n = 11) twice a day for one year. Almitrine bismesylate increased PaO2 by 8.1 +/- 2.1 mm Hg (mean +/- SEM), decreased arterial carbon dioxide tension by 3.0 +/- 0.7 mm Hg (mean +/- SEM), and increased minute ventilation by 3.1 +/- 0.5 liters/minute (mean +/- SEM) during wakefulness. All of these changes were statistically significant. Five patients in the almitrine bismesylate group and eight patients in the placebo group completed sleep studies prior to and after 56, 180, and 360 days of almitrine bismesylate or placebo administration. Relative to placebo, almitrine bismesylate significantly increased oxygen saturation during sleep without any significant changes in the quantity or quality of sleep.