Pharmacodynamics assessment of Bemiparin after multiple prophylactic and single therapeutic doses in adult and elderly healthy volunteers and in subjects with varying degrees of renal impairment.

INTRODUCTION: Aging and renal impairment may prolong the half-life and lead to accumulation of low molecular weight heparins. Correct dosing is critical to prevent bleeding or thrombosis. MATERIALS AND METHODS: Open, parallel study. Healthy adult [n=13] and elderly (>65yrs) [n=12] volunteers; and subjects with mild (ClCr≥50 to ≤80mL/min, n=8), moderate (ClCr≥30 to <50mL/min, n=7), and severe (ClCr<30mL/min, n=8) renal impairment received four prophylactic doses (3,500IU/24h) and a single therapeutic dose (115IU/kg) of bemiparin with an interim washout period. Anti-FXa activity and the potential need for dose adjustment were evaluated. RESULTS: There were statistically significant differences in the severe renal impairment group vs. adult volunteers in all anti-FXa related parameters, but no significant differences in any of the anti-FXa related parameters between the adult and the elderly. Anti-FXa simulations after 10 prophylactic doses predicted mean Amax=0.59IU/mL in subjects with severe renal impairment and 0.33-0.39IU/mL in the rest. Simulations in the severe renal impairment group with dose adjustment (2,500IU/24h) predicted all individual Amax<0.60IU/mL (mean Amax=0.42IU/ml). Simulations after 10 therapeutic doses predicted mean Amax=1.22IU/mL in severe renal impairment group and 0.89-0.98IU/mL in the rest. Simulations in the severe renal impairment group with 75% dose adjustment predicted individual Amax≤1.60IU/mL (mean Amax=0.91IU/mL). CONCLUSIONS: No dose adjustments are required in elderly with preserved renal function. A dose adjustment of bemiparin is only advisable in patients with severe renal impairment when using prophylactic or therapeutic doses.

Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study.

INTRODUCTION: RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males. MATERIALS AND METHODS: We conducted a two-stage, single-center, open-label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated. RESULTS: All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A(max) was 0.16 (±0.02) IU/mL and AUC(0-24) was 1.11 (±0.24) IU*h/mL, At the highest dose anti-FXa activity A(max) was 1.67 (±0.15) IU/mL; AUC(0-24) was 21.48 (±4.46) IU*h/mL and t½ was 8.05h. Mean T(max) (all doses) was 2.86 (±0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A(max) among doses (p=0.594) and normalized AUC(0-24) (p=0.092), correlations between A(max-)dose (R(2)=0.89, p<0.001) and AUC(0-24)-dose (R(2)=0.86, p<0.001)]. Anti-FIIa activity was below the detection limit (0.1IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin. CONCLUSIONS: In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity.