Pharmacokinetics of a New, Ultra-Low Molecular Weight Heparin, Semuloparin (AVE5026), in Healthy Subjects. Results From the First Phase I Studies.

AVE5026 is a new generation hemisynthetic ultra-low molecular weight heparin (average molecular weight 2500 Da) with high anti-Factor Xa (anti-Xa) and residual anti-Factor IIa (anti-IIa) activities (ratio anti-Xa/IIa > 30). As a consequence, AVE5026 has the potential to improve the risk benefit ratio compare to low molecular weight heparins. AVE5026 is currently in phase III clinical trials of venous thromboembolism prevention.

Pharmacokinetic (PK) data from the first 3 Phase I studies were examined to evaluate the dose proportionality of anti-Xa concentration, absolute bioavailability, and accumulation of AVE5026 after single and repeated subcutaneous (SC) dosing in healthy young and elderly subjects.

The first study was a double-blind, randomized, single-dose escalation study in healthy male subjects (aged 18–42 years) given single SC doses of AVE5026 in 7 ascending steps from 0.05 to 1.4 mg/kg or a matched placebo. The second study was a randomized, double-blind, placebo-controlled, repeat dose-escalation study of AVE5026 at doses of 5 mg (only in elderly), 20, 60, and 100 mg given SC once daily for 14 days in healthy young male (aged 18–40 years) and elderly male and female (aged 65–80 years) subjects, and AVE5026 40 mg SC once daily for 28 days in young healthy males. The third study was a randomized open-label study carried out in 15 healthy male and female subjects (aged 18–45 years) to determine bioavailability after a 60 mg single SC dose compared to a 3-hour intravenous (IV) infusion. In all studies, plasma and urine samples were analyzed for anti-Xa activity concentration using a chromogenic enzyme assay to determine the maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC), and terminal plasma half-life (t_1/2-z). In the repeat dosing study, accumulation ratios were calculated for each age and dose group. In the third study, AUC mean ratios between the SC and IV routes were calculated to assess bioavailability. Anti-IIa plasma activity was also analyzed after the 2 highest doses in the first study and in the 2 other studies using a chromogenic enzyme assay.

The single-dose escalation study included 56 subjects. Anti-Xa concentration increased in proportion to the dose from 0.1 to 1.4 mg/kg: the mean C_max ranged 0.406–10.9 μgEq/mL and AUC_0-∞ ranged 11.0–173 μgEq·h/mL. Mean t_1/2-z was approximately 11 hours (range 9.8–11.4) for doses 0.3 mg/kg and up. Similarly, anti-IIa levels increased proportional to dose at the 1.2 and 1.4 mg/kg (84 and 98 mg) doses with a mean C_max of 0.013–0.017 U/mL. The mean amount of drug excreted in the 24-h urine collection as active anti-Xa fragments (fe_0-24 ) ranged 20.7–31.5% of the dose. In the repeated dose escalation study, data from 72 subjects were available for the anti-Xa PK analysis. Steady state was reached before the fourth injection in young and before the fifth in elderly subjects. In young subjects, C_max increased 1.21-fold from Day 1 to Day 14 and AUC_0-24 increased 1.37-fold over all doses. A dose-proportional increase in C_max and AUC_0-24 was observed on Day 1 and Day 14. On Day 14, t_1/2-z ranged 16.4–20.5 hours across the doses. On Day 14, fe_0-24 ranged 25.0–49.1% of the dose from 20 to 100 mg. Plasma anti-IIa levels were assessed at 100 mg: C_max was 0.015 U/mL on Day 1 and 0.014 U/mL on Day 14. In elderly subjects, anti-Xa C_max increased 1.37-fold from Day 1 to Day 14, and AUC_0-24 increased 1.47-fold over the dose range. A dose-proportional increase in C_max and AUC_0-24 was observed on Day 1 and Day 14. On Day 14, t_1/2-z ranged 14.6–21.9 hours across the doses. On Day 14, fe_0-24 ranged 20.5–40.8% of the dose from 5 to 100 mg. Most elderly subjects had mild renal impairment. After a single SC 60 mg dose of AVE5026, absolute bioavailability was 97.7% (90% confidence interval 89.7–107%). Fe_0-24 was 30.6% of the dose. The total clearance of AVE5026 was 0.600 ± 0.173 L/h with a distribution volume of 7.88 ± 1.45 L. Overall, AVE5026 was well-tolerated and safe.

AVE5026 presents a linear PK profile indicated by dose proportionality after single and repeat dosing, and is completely absorbed after SC injection. The accumulation ratio is in line with the terminal half-life. After repeat dosing in elderly subjects, a slight increase in accumulation of AVE5026 was seen, and steady state was reached a day later. The limited impact of age observed may reflect the mild renal impairment.

Dubruc:sanofi-aventis: Employment. Karimi-Anderesi:sanofi-aventis: Employment. Lunven:sanofi-aventis: Employment. Zhang:sanofi-aventis: Employment. Grossmann:sanofi-aventis: Consultancy. Potgieter:Farmovs-Parexel Research Center: Employment.