Pharmacokinetics of a low molecular weight heparin, Logiparin, after intravenous and subcutaneous administration to healthy volunteers

Pharmacokinetics of a low molecular weight heparin (LMWH) were studied in healthy volunteers. After an intravenous bolus injection of 5000 anti-Xa U in 5 healthy volunteers anti Xa activity disappeared according to the combination of saturable and a linear mechanism, preceded by a rapid initial disappearance. The apparent half-life of the anti Xa activity is about twice as long as that of standard heparin. In another set of experiments 5000 anti Xa U of LMWH were immediately followed by 50 mgr of Protamine Sulphate (PS). The curve of the anti Xa-activity parallelled the original curve at a level of about 30-40%. No rebound phenomenon was observed. The same dose of the LMWH followed by 100 mg of PS resulted in an anti Xa disappearance curve at an obvious higher level of about 50%. Also at this dose no rebound phenomenon was noticed.A continuous infusion of 10.000 anti Xa U/24 h during 10 hours was followed by 15.000 anti Xa U/24 h for another 10 hours after which the dose was raised to 20.000 anti Xa U/24 h for another 10 hours. Only the first infusion period resulted in a plateau fase. At the end of these experiments anti Xa activity was neutralized by 50 mg P.S. i.v. resulting in the disappearance of less than 50% of anti Xa activity. After subcutaneous administration of 15.000 anti Xa U (corresponding to the dose for i.v. treatment per day with this LMWH) peak levels of 1,1-1,8 anti Xa were reached after 3-4 hours. Supra-optimal anti Xa levels (higher than 0.9) were observed in all volunteers during a period of 5 hours. After 24 hours in none of the volunteers any anti Xa-activity could be detected.Conclusions:In contrast to previous reports pharmacokinetics of this LMWH do not essentially differ from those of standard heparin apart from its longer half-life and its high bioavialability after subcutaneous injection.

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Chrono-Pharmacological Study of Once Daily Curative Dose of a Low Molecular Weight Heparin (200IU antiXa/kg of Dalteparin) in Ten Healthy Volunteers

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649794 ◽

1995 ◽

Vol 74 (02) ◽

pp. 660-666 ◽

Cited By ~ 15

Author(s):

P Mismetti ◽

J Reynaud ◽

B Tardy-Poncet ◽

S Laporte-Simitsidis ◽

M Scully ◽

...

Keyword(s):

Molecular Weight ◽

Healthy Volunteers ◽

Low Molecular Weight Heparin ◽

Pharmacological Study ◽

Area Under The Curve ◽

Factor Xa ◽

Similar Efficacy ◽

Low Molecular Weight ◽

Thrombin Time ◽

Once Daily

SummaryLow molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH).Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin®) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve.Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p <0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection.A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.

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Pharmacodynamics and Tolerance of Two Nadroparin Formulations (10,250 and 20,500 Anti Xa IU·ml-1) Delivered for 10 Days at Therapeutic Dose

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614988 ◽

1998 ◽

Vol 79 (02) ◽

pp. 338-341 ◽

Cited By ~ 10

Author(s):

C. Navarro ◽

J. P. Cambus ◽

H. Caplain ◽

P. d’Azemar ◽

J. Necciari ◽

...

Keyword(s):

Molecular Weight ◽

Venous Thromboembolism ◽

Healthy Volunteers ◽

Total Dose ◽

Therapeutic Dose ◽

Low Molecular Weight Heparin ◽

Dose Effect ◽

Low Molecular Weight ◽

High Dose ◽

Circadian Effect

SummaryVenous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i. d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU·ml-1 respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU·kg-1 b.i. d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU·kg-1 o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC0-12 h plus AUC12-24 h (treatment A) and the AUC0-24 h (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC0-12 h were slightly but significantly lower than the AUC12-24 h suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 ± 0.25), in relation with the anti-IIa activity (0.3 ± 0.1 IU·ml–1).

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Effect of Low-Molecular-Weight Heparin (Tinzaparin) and Unfractionated Heparin on Platelet Aggregation

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969600200311 ◽

1996 ◽

Vol 2 (3) ◽

pp. 209-212 ◽

Cited By ~ 1

Author(s):

Hanne B. Ravn ◽

Claus Bregengaard ◽

Henrik Vissinger ◽

Per Østergaard ◽

Jan Holst ◽

...

Keyword(s):

Molecular Weight ◽

Platelet Aggregation ◽

Unfractionated Heparin ◽

Low Molecular Weight Heparin ◽

Ex Vivo ◽

Subcutaneous Administration ◽

Low Molecular Weight ◽

Pronounced Difference ◽

Dose Dependent

A low-molecular-weight heparin (LMWH), when anti-IIa activity was compared. In the ex vivo part Tinzaparin, was compared with unfractionated heparin of the study, a significant enhancement of ADP-induced (UFH) for their effects on platelet aggregation in vitro and platelet aggregation was observed after i.v. administra ex vivo. Both heparins showed a dose-dependent proag- tion of both Tinzaparin and UFH with no difference in gregatory effect on ADP- and collagen-induced platelet potency. Subcutaneous administration of Tinzaparin in aggregation in vitro, but LMWH was less potent. The two different doses did not have any effect on platelet differences in potency between Tinzaparin and UFH de- activity. In conclusion, Tinzaparin appears, like other pended on how the compounds were compared. The most LMWHs, to have less proaggregatory effect on platelets pronounced difference was found when molar concentra- than UFH both in vitro and ex vivo.

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Bioavailability and pharmacokinetics of a new low molecular weight heparin (RO-11)—A three way cross-over study in healthy volunteers

Thrombosis Research ◽

10.1016/0049-3848(95)00036-4 ◽

1995 ◽

Vol 78 (1) ◽

pp. 77-86 ◽

Cited By ~ 19

Author(s):

Liliana Falkon ◽

Desirée Sáenz-Campos ◽

Rosa Antonijoan ◽

Silvia Martín ◽

Manel Barbanoj ◽

...

Keyword(s):

Molecular Weight ◽

Healthy Volunteers ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight

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Heparin and Fibrinolysis - Comparison of Subcutaneous Administration of Unfractionated and Low Molecular Weight Heparin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642772 ◽

1988 ◽

Vol 59 (02) ◽

pp. 284-288 ◽

Cited By ~ 13

Author(s):

E Eriksson ◽

I M Wollter ◽

B Christenson ◽

L Stigendal ◽

B Risberg

Keyword(s):

Molecular Weight ◽

Plasminogen Activator ◽

Normal Saline ◽

Low Molecular Weight Heparin ◽

Bolus Injection ◽

Subcutaneous Administration ◽

Fibrinolytic System ◽

Low Molecular Weight ◽

Thrombin Time ◽

Diurnal Range

SummaryThe effects on the fibrinolytic system after a single s.c. bolus injection (at 9 a.m.) of either 5000 IU conventional heparin or 5000 anti-Xa U of a fractionated low molecular weight heparin (Fragmin, KabiVitrum, Sweden) were investigated in 9 healthy volunteers. The effects were compared to those of an injection of normal saline in 6 volunteers. Samples for biochemical analyses were taken regularily during 6 hours after drug or placebo administration.In the coagulation system the following parameters were measured: Activated partial thromboplastin time (APTT), anti- Xa activity, thrombin time and fibrinogen. The fibrinolytic system was monitored by analysing: plasminogen, ɑ2-antiplasmin, fibrinogen) degradation products (FDP), euglobulin clot lysis time (ECLT), tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor (PAI) activity. Injection of the 2 drugs was followed by elevations in APTT and anti-Xa activity, and were more pronounced for Fragmin than heparin. The fibrinolytic system exhibited a diurnal variation with decreasing PAI activity and increasing t-PA activity during the day. Volunteers receiving normal saline (placebo) showed a similar pattern. The results were unrelated to heparin.It is concluded from this study that neither heparin nor Fragmin had any significant effect on the fibrinolytic parameters when measured after a single s.c. bolus injection since the observed variations were within the diurnal range.

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Pharmacodynamic Properties of Long Lasting Butyryl Heparin Derivatives in the Rabbit

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648492 ◽

1992 ◽

Vol 67 (05) ◽

pp. 550-555 ◽

Cited By ~ 2

Author(s):

S Saivin ◽

C Caranobe ◽

M Petitou ◽

J C Lormeau ◽

G Houin ◽

...

Keyword(s):

Molecular Weight ◽

Unfractionated Heparin ◽

Intravenous Injection ◽

Low Molecular Weight Heparin ◽

Subcutaneous Administration ◽

Constant Infusion ◽

Daily Injection ◽

Low Molecular Weight ◽

Vein Thrombosis ◽

Bolus Intravenous Injection

SummaryThis paper reports on the pharmacodynamic properties of butyryl derivatives of unfractionated heparin (C4-UH) and of low molecular weight heparin (C4-CY 216) after bolus intravenous injection, constant infusion and subcutaneous administration to rabbits. The pharmacodynamic properties of the two butyryl derivatives were compared to those of the parent compounds, unfractionated heparin (UH) and low molecular weight heparin (CY 216). After bolus intravenous injection of increasing doses, the disposition of the butyryl derivatives were comparable to that of their parent compounds up to 3 mg kg-1. Over this dose, their clearances became 2 to 3 times lower. These long lasting properties were confirmed by constant intravenous infusion experiments. After subcutaneous administration, the bioavailability of C4-UH remained low (10%) at any dose while that of C4-CY 216 ranged from 42 to 120%. If these findings are confirmed in man, these new derivatives open the possibility of treating established deep vein thrombosis with only one daily injection of a butyryl derivative of low molecular weight heparin.

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