Population Pharmacokinetics and Probability of Target Attainment Analysis of Nadroparin in Different Stages of COVID-19.

BACKGROUND AND OBJECTIVE: The risk of thrombotic complications in critical patients with COVID-19 remains extremely high, and multicenter trials failed to prove a survival benefit of escalated doses of low-molecular-weight heparins (nadroparin calcium) in this group. The aim of this study was to develop a pharmacokinetic model of nadroparin according to different stages of COVID-19 severity. METHODS: Blood samples were obtained from 43 patients with COVID-19 who received nadroparin and were treated with conventional oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation. We recorded clinical, biochemical, and hemodynamic variables during 72 h of treatment. The analyzed data comprised 782 serum nadroparin concentrations and 219 anti-Xa levels. We conducted population nonlinear mixed-effects modeling (NONMEM) and performed Monte Carlo simulations of the probability of target attainment for reaching 0.2-0.5 IU/mL anti-Xa levels in study groups. RESULTS: We successfully developed a one-compartment model to describe the population pharmacokinetics of nadroparin in different stages of COVID-19. The absorption rate constant of nadroparin was 3.8 and 3.2 times lower, concentration clearance was 2.22 and 2.93 times higher, and anti-Xa clearance was 0.87 and 1.1 times higher in mechanically ventilated patients and the extracorporeal membrane oxygenation group compared with patients treated with conventional oxygen, respectively. The newly developed model indicated that 5.900 IU of nadroparin given subcutaneously twice daily in the mechanically ventilated patients led to a similar probability of target attainment of 90% as 5.900 IU of subcutaneous nadroparin given once daily in the group supplemented with conventional oxygen. CONCLUSIONS: Different nadroparin dosing is required for patients undergoing mechanical ventilation and extracorporeal membrane oxygenation to achieve the same targets as those for non-critically ill patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT05621915.

Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID-19 intensive care unit patients.

AIMS: Nadroparin is administered to COVID-19 intensive care unit (ICU) patients as thromboprophylaxis. Despite existing population pharmacokinetic (PK) models for nadroparin in literature, the population PK of nadroparin in COVID-19 ICU patients is unknown. Moreover, optimal dosing regimens achieving anti-Xa target levels (0.3-0.7 IU/mL) are unknown. Therefore, a population PK analysis was conducted to investigate different dosing regimens of nadroparin in COVID-19 ICU patients. METHODS: Anti-Xa levels (n = 280) from COVID-19 ICU patients (n = 65) receiving twice daily (BID) 5700 IU of subcutaneous nadroparin were collected to perform a population PK analysis with NONMEM v7.4.1. Using Monte Carlo simulations (n = 1000), predefined dosing regimens were evaluated. RESULTS: A 1-compartment model with an absorption compartment adequately described the measured anti-Xa levels with interindividual variability estimated for clearance (CL). Inflammation parameters C-reactive protein, D-dimer and estimated glomerular filtration rate based on the Chronic Kidney Disease Epidemiology Collaboration equation allowed to explain the interindividual variability of CL. Moreover, CL was decreased in patients receiving corticosteroids (22.5%) and vasopressors (25.1%). Monte Carlo simulations demonstrated that 5700 IU BID was the most optimal dosing regimen of the simulated regimens for achieving prespecified steady-state t = 4 h anti-Xa levels with 56.7% on target (0.3-0.7 IU/mL). CONCLUSION: In our study, clearance of nadroparin is associated with an increase in inflammation parameters, use of corticosteroids, vasopression and renal clearance in critically ill patients. Furthermore, of the simulated regimens, targeted anti-Xa levels were most adequately achieved with a dosing regimen of 5700 IU BID. Future studies are needed to elucidate the underlying mechanisms of found covariate relationships.

Pharmacokinetic Comparison of Subcutaneous and Intravenous Nadroparin Administration for Thromboprophylaxis in Critically Ill Patients on Vasopressors.

INTRODUCTION: Critically ill patients are exposed to a high risk of developing thromboembolism. Moreover, standard prophylaxis with subcutaneous (SC) heparin is less efficient in patients requiring vasopressors. The aim is a comparison of pharmacokinetics between SC and intravenous (IV) applied nadroparin. METHODS: Thirty-eight ventilated ICU patients requiring vasopressor support were randomized into a single dose of nadroparin 3,800 IU (0.4 mL) subcutaneously (SC group) or 1,900 IU (0.2 mL) intravenously (IV group). Anti-factor Xa activity (anti-Xa) was observed over 24 h; data are stated as median (IQR). RESULTS: Peak anti-Xa was significantly higher in the IV group 0.42 (0.39-0.43) IU/mL than in the SC group 0.16 (0.09-0.18) IU/mL (p < 0.001). There was a trend towards higher area under the curve (AUC) of anti-Xa in the SC group 1.41 (0.41-1.80) IU/mL × h than in the IV group 1.04 (0.93-1.13) IU/mL × h (p = 0.08). In the SC group, there was a negative correlation between anti-Xa AUC and both capillary refill time Xa (r = -0.86) and norepinephrine dose (r = -0.68). In the IV group, anti-Xa decrease half-life was 1.6 (1.4-2.0) h. CONCLUSIONS: IV administration of 1,900 IU of nadroparin led to a predictable effective peak anti-Xa. After SC administration, anti-Xa was heterogeneous and significantly influenced by peripheral perfusion.

The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients.

BACKGROUND: Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. OBJECTIVES: First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. SETTING: This study was performed in a general hospital specialized in bariatric surgery. METHODS: Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of ≥ 140 kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700 IU of nadroparin for 4 weeks. Anti-Xa activity was determined 4 h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850 IU nadroparin in another 50 patients (52%). RESULTS: TBW of the complete group was 148.5 ± 12.6 kg. Mean anti-Xa activity following 5700 IU nadroparin was 0.19 ± 0.07 IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW ≥ 80 kg had insufficient anti-Xa activity concentrations. No VTE events occurred. CONCLUSIONS: In morbidly obese patients, a postoperative dose of 5700 IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW ≥ 80 kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels.

No accumulation of a prophylactic dose of nadroparin in moderate renal insufficiency.

BACKGROUND: Low-molecular-weight heparins (LMWHs) have been shown to accumulate in patients with renal insufficiency, especially in therapeutic dosages. Although no appropriate studies have been conducted for prophylactic dosages of nadroparin, dose reduction is sometimes recommended, especially for high prophylactic dosages. We assessed accumulation of a prophylactic dose of 5700 IU subcutaneous nadroparin once daily in patients with renal insufficiency. METHODS: We conducted a prospective cohort study and measured peak anti-Xa activity four hours after subcutaneous nadroparin injection on day 1, 3, 5 and if possible day 10 in adults with and without renal insufficiency defined as a glomerular filtration rate (GFR) below or above 50 ml/min/1.73 m2. Patients with a GFR below 10 ml/min/1.73 m2 were excluded. RESULTS: We included 14 patients in each group. In the group with renal failure 12 patients had a GFR between 30 and 50 ml/min/1.73 m2. Peak anti-Xa activity showed a high interindividual variability, but was fairly constant within each patient. There was no rise in peak anti-Xa activity on day 3 and 5 after consecutive administration. In the group with normal renal function, peak anti-Xa activity declined on day 5 compared with day 1 (p = 0.005). CONCLUSION: Prophylactic dosages of nadroparin showed no accumulation in patients with a GFR between 30-50 ml/min/1.73 m2. Dose reduction in this group could lead to suboptimal thromboprophylaxis. Due to underrepresentation of patients with a GFR < 30 ml/min/1.73 m2 (n = 2), we cannot give recommendations for this group.

Hemostasis during low molecular weight heparin anticoagulation for continuous venovenous hemofiltration: a randomized cross-over trial comparing two hemofiltration rates.

INTRODUCTION: Renal insufficiency increases the half-life of low molecular weight heparins (LMWHs). Whether continuous venovenous hemofiltration (CVVH) removes LMWHs is unsettled. We studied hemostasis during nadroparin anticoagulation for CVVH, and explored the implication of the endogenous thrombin potential (ETP). METHODS: This cross-over study, performed in a 20-bed teaching hospital ICU, randomized non-surgical patients with acute kidney injury requiring nadroparin for CVVH to compare hemostasis between two doses of CVVH: filtrate flow was initiated at 4 L/h and converted to 2 L/h after 60 min in group 1, and vice versa in group 2. Patients received nadroparin 2850 IU i.v., followed by 380 IU/h continuously in the extracorporeal circuit. After baseline sampling, ultrafiltrate, arterial (art) and postfilter (PF) blood was taken for hemostatic markers after 1 h, and 15 min, 6 h, 12 h and 24 h after converting filtrate flow. We compared randomized groups, and 'early circuit clotting' to 'normal circuit life' groups. RESULTS: Fourteen patients were randomized, seven to each group. Despite randomization, group 1 had higher SOFA scores (median 14 (IQR 11-15) versus 9 (IQR 5-9), p = 0.004). Anti-Xa art activity peaked upon nadroparin bolus and declined thereafter (p = 0.05). Anti-Xa PF did not change in time. Anti-Xa activity was not detected in ultrafiltrate. Medians of all anti-Xa samples were lower in group 1 (anti-Xa art 0.19 (0.12-0.37) vs. 0.31 (0.23-0.52), p = 0.02; anti-Xa PF 0.34 (0.25-0.44) vs. 0.51 (0.41-0.76), p = 0.005). After a steep decline, arterial ETPAUC tended to increase (p = 0.06), opposite to anti-Xa, while postfilter ETPAUC increased (p = 0.001). Median circuit life was 24.5 h (IQR 12-37 h). Patients with 'short circuit life' had longer baseline prothrombin time (PTT), activated thromboplastin time (aPTT), lower ETP, higher thrombin-antithrombin complexes (TAT) and higher SOFA scores; during CVVH, anti-Xa, and platelets were lower; PTT, aPTT, TAT and D-dimers were longer/higher and ETP was slower and depressed. CONCLUSIONS: We found no accumulation and no removal of LMWH activity during CVVH. However, we found that early circuit clotting was associated with more severe organ failure, prior systemic thrombin generation with consumptive coagulopathy, heparin resistance and elevated extracorporeal thrombin generation. ETP integrates these complex effects on the capacity to form thrombin. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT00965328.

Encapsulation of low molecular weight heparins: influence on the anti-Xa/anti-IIa ratio.

Tinzaparin and nadroparin, two low molecular weight heparins (LMWH), were encapsulated within microparticles by the double emulsion method using ammonium methacrylate copolymer (Eudragit RS) alone or mixed with poly (d,l-lactic-co-glycolic acid) at different ratios. The resulting microparticles were characterized in vitro according to particle size, encapsulation rate and release profiles both by chemical and biological methods. The biological method was based on the measurement of the anti-Xa/anti-IIa ratio typical of each LMWH. This ratio also reflects the relative proportion between active chains below and above the critical chain length of 5000 Da (i.e. BCL and ACL chains), since LMWH are mixtures of chains with various lengths and activities. For both LMWH, high entrapment efficiencies, expressed as anti-Xa and anti-IIa activities, were obtained and amounted to anti-Xa/anti-IIa ratios close to the commercial ratio. During the in vitro release, whatever the formulation, more BCL chains were released than ACL chains: a higher (compared to commercial ratio) and stable anti-Xa/anti-IIa ratio was observed. This increase of the anti-Xa/anti-IIa ratio was influenced by the type of LMWH used and the composition of the Eudragit RS formulation. This type of microparticles could constitute a new pharmaceutical form of LMWH with a higher anti-Xa/anti-IIa ratio than commercial forms.

A chronopharmacodynamic study on standard heparin, a low molecular weight heparin (nadroparin) and danaproid: establishing and comparing the daily variations of these drugs in rats.

The effects of dosing time on the anticoagulant activity of unfractionated heparin, low molecular weight heparin (nadroparin) and danaproid were investigated. The chronopharmacological comparisons of the drugs were done on the anti-Xa, anti-IIa activities and activated partial thromboplastin time assays. Several dosing times were considered and an analysis based on a population approach was adopted. Under unfractionated heparin, the pharmacological activities did not exhibit significant daily variations. In contrast, significant daily profiles were observed in all the biological assays performed with low molecular weight heparin. Anti-Xa and anti-IIa activities showed some fluctuations over a 24-hour period with a peak at noon. As for the variations of the activated partial thromboplastin time, two peaks were noted early in the morning and at the beginning of nightfall. As for danaproid, only a daytime maximum of anti-Xa activity could be found.

[State of the art: low-molecular-weight heparin and beyond]. / Stato dell'arte: eparine a basso peso molecolare ed oltre.

Approximately 20 years ago a new family of antithrombotic compounds started to be investigated: the low-molecular weight heparins (LMWH). The rationale for their use was based on the evidence that the inhibition of the Factor Xa of blood coagulation was less marked than that of Factor IIa when using the LMWHs as compared to unfractioned heparin (HF). This particular mechanism of action was considered to be of advantage regarding the safety profile (the pro-haemorrhagic effect) compared to HF. Today we know that the real advantage of LMWHs is due to their high bioavailability which makes safe and reliable their subcutaneous administration without laboratory monitoring. The LMWHs are equally effective than HF for the treatment of acute Deep Vein Thrombosis. For the prophylaxis of Venous Thromboembolism, LMWHs are indicated as first choice in high-risk patients such as those undergoing major orthopaedic surgery. The future development of this family of drugs encompasses the launch of the pentasaccharide which is a pure anti-/Xa inhibitor.

Population pharmacokinetic of nadroparin calcium (Fraxiparine) in children hospitalised for open heart surgery.

Administration of low molecular weight heparin following heart surgery in paediatric patients in order to prevent thromboembolic events results in a large variation in anti-Xa activities. A population study was undertaken to determine pharmacokinetic parameters after nadroparin calcium (Fraxiparine) administration and the effects of potential covariates; this study included 154 children divided into two groups: a model group (124 patients) and a validation group (30 patients). The 432 anti-Xa activities were analysed using NONMEM on the basis of a one-compartment model with three parameters: apparent clearance, apparent volume of distribution and absorption rate. The influence of body weight, age, sex and dose regimen (once or twice daily) were investigated. The best fit corresponds to the formula: apparent clearance (l/min)=0. 541 x weight1.51/(6.151.51 + weight1.51) and apparent volume (l)=0.355 x weight. The inter-individual variability (expressed in coefficient of variation) of these parameters are high, especially with regard to the apparent volume (92%), but no other available covariate was found to explain this variability.

[Low molecular weight heparin (LMWH) modulates migration of peripheral blood mononuclear cells and neutrophils of asthmatics]. / Drobnoczasteczkowa heparyna moduluje migracje komórek jednojadrzastych i neutrofilów krwi obwodowej chorych na astme.

Evidence has now accumulated that heparin can significantly affect immune response including allergic inflammation. Cell migration is supposed to be very crucial in this process. Thus the aim of that study was to investigate whether low molecular weight heparin-nadroparine is chemoattractant for some inflammatory cells in asthmatics. Peripheral blood mononuclear cells (PBMC) and neutrophils from 15 asthmatics were obtained by gradient centrifugation. Chemotaxis was compared with that induced with known chemoattractants-fMLP and IL-8. We found that nadroparine caused significant and dose dependent chemotaxis of PBMC and comparable with influence of fMLP and IL-8. Nadroparine amplified chemotaxis of neutrophils but not significantly. Chemotaxis induced by fMLP and IL-8 was diminished when blood cells were incubated earlier with 50 mg of nadroparine.

Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin).

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

Pharmacodynamics and tolerance of two nadroparin formulations (10,250 and 20,500 anti Xa IU x ml(-1)) delivered for 10 days at therapeutic dose.

Venous 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 x 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 x kg(-1) b.i.d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU x 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 AUC(0-12 h) plus AUC(12-24 h) (treatment A) and the AUC(0-24 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 AUC(0-12 h) were slightly but significantly lower than the AUC(12-24 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 x ml(-1)).

Nadroparin calcium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders.

Nadroparin (nadroparin calcium) is a low molecular weight heparin with a mean molecular weight of 4.5 kD. Compared with unfractionated heparin (UFH), nadroparin has a greater ratio of anti-factor Xa to anti-factor Ha activity, greater bioavailability and a longer duration of action, allowing it to be administered by subcutaneous injection for prophylaxis or treatment of thromboembolic disorders. In clinical trials conducted in older patients (mean age usually > 60 years), nadroparin was at least as effective as UFH in preventing deep vein thrombosis (DVT) and pulmonary embolism after major general or orthopaedic surgery, and in bedridden medical patients. Nadroparin was also at least as effective as dalteparin or oral acenocoumarol in preventing thromboembolic events following general and orthopaedic surgery, respectively. When used for treatment of established DVT, nadroparin was at least as effective as intravenous UFH. Subcutaneous nadroparin, at dosages similar to those used for the treatment of DVT, produced promising results in older patients with pulmonary embolism, acute ischaemic stroke or unstable angina. In 1 study, 75% of nadroparin-treated patients were able to complete their treatment at home and 36% did not require admission to hospital; the potential pharmacoeconomic implications of these results deserve further evaluation. Overall treatment costs (drug acquisition and monitoring costs) were similar for nadroparin and UFH in a French study, but nadroparin was associated with significantly less nursing time spent on treatment delivery. Nadroparin is well tolerated by older patients. The most frequently reported adverse events in a large (n approximately 4500) placebo-controlled study in general surgical patients were wound and injection site haematoma (11.8 and 10.2%, respectively, vs approximately 6.5% for placebo). When used as prophylaxis, no significant differences in bleeding complications were noted between nadroparin and UFH or acenocoumarol recipients. Prophylactic nadroparin was associated with significantly fewer withdrawals because of adverse events than UFH in elderly bedridden medical patients. When used as treatment for DVT, nadroparin was generally associated with lower occurrences of major bleeding than intravenous UFH (0.5 to 2.3% vs 2 to 5%); however, trials were not large enough to demonstrate any significant differences between the 2 agents. Similarly, the incidence of thrombocytopenia was slightly, but generally not significantly, lower in nadroparin (< 1%) than in UFH (< or = 3.5%) recipients. Thus, nadroparin should be considered an effective and well tolerated alternative to UFH for prophylaxis and treatment of DVT in older patients, with the advantage of more convenient administration and decreased monitoring requirements.

Long-term persistence of low-molecular-weight material with anti-factor Xa activity contributes to anticoagulant and antithrombotic effects after subcutaneous injection of CY 216 in the rabbit.

This study was done to document further the mechanism of the antithrombotic effect of CY 216 after subcutaneous injection in the rabbit. We first measured the circulating anti-factor Xa and anti-thrombin activities expressed in either International Unit or Standard Independent Unit and from these activities we calculated the above critical length material (ACLM) and below critical length material (BCLM) levels. The clearance of the BCLM was half that of the ACLM. Then we determined the inhibitory effect of CY 216 on thrombin generation (TG) in platelet-poor plasma (PPP) and in whole blood. TG was both inhibited and delayed in whole blood, while it was only inhibited in PPP. The IC50 on TG in PPP and in whole blood were 1.80 +/- 0.16 and 4.33 +/- 1.01 micrograms.ml-1 respectively. After the injection, the inhibition of TG was significant as long as BCLM was detectable. The duration of the antithrombotic effect was essentially correlated to the ACLM level in the Wessler-thromboplastin model and to the BCLM level in the Wessler-serum model. Taken together, these results demonstrate that both ACLM and BCLM components of CY 216 are involved in its anticoagulant effect ex vivo as well as in its antithrombotic activity in vivo, and that the relative contribution of BCLM increases with the time after administration.

Comparison of the pharmacokinetic profiles of three low molecular mass heparins--dalteparin, enoxaparin and nadroparin--administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism).

The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin), nadroparin (Fraxiparin), and enoxaparin (Lovenox) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of nadroparin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by nadroparin is 1.54 times greater (p < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 +/- 5.5 and 13.8 +/- 3.2 ml/min) is significantly smaller than those of nadroparin (CL/F = 21.4 +/- 7.0 ml/min; p < 0.01) and dalteparin (CL/F = 33.3 +/- 11.8 ml/min; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) than that of nadroparin. These LMMHs also differ by their renal excretion pattern: more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses (6.4 and 8.7% of the dose, respectively) than following nadroparin (3.9%) and dalteparin (3.4%) injection. These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different: dalteparin: 2.8 h; nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies.

Pharmacokinetic study of the low-molecular-weight heparin fraxiparin in patients with nephrotic syndrome.

We studied the pharmacokinetics of the low-molecular-weight heparin (LMWH) Fraxiparin in 6 patients with the nephrotic syndrome. Maximal plasma anti-Xa activity was obtained 5 h after a subcutaneous injection of 60 IU anti-Xa/kg. Anti-Xa activity was no longer detectable 24 h postinjection. These results are similar to those obtained with the same dosage in other clinical settings. The biological response to a daily subcutaneous injection of 60 IU anti-Xa/kg was studied for 8 days. No cumulative effect was observed. All the patients had an abnormal activation state of hemostasis mechanisms before treatment, as shown by high prothrombin fragment 1 + 2 and D-dimer levels, which were not decreased by Fraxiparin. It remains to be determined whether a higher dosage of LMWH might attenuate the hypercoagulability in these patients.

Pharmacological properties of CY 216 and of its ACLM and BCLM components in the rabbit.

This study compares some in vivo pharmacological properties of CY 216 and of its ACLM and BCLM components having a molecular weight above and below 5.4 kDa respectively. The anti-factor Xa/antithrombin ratio of these compounds determined in a rabbit plasma system were 2.5 and 1.2 for CY 216 and ACLM respectively while BCLM was devoid of anti-thrombin effect. After bolus intravenous injection, continous infusion and subcutaneous administration, the clearances of anti-factor Xa activity generated by ACLM were, on the average, 2 and 1.5 times higher than those generated by BCLM and CY 216 respectively. The clearances of the anti-thrombin activity were comparable for CY216 and ACLM, and higher than those of the antifactor Xa activity. The duration of the antithrombotic effect was investigated in the Wessler model after a single subcutaneous injection of 1000 anti-factor Xa units of one of the compounds. Using thromboplastin as thrombogenic stimulus, the most efficient agent was ACLM and the antithrombotic activity was essentially correlated to the circulating anti-thrombin activity. Using human serum as thrombogenic stimulus, ACLM and BCLM were more efficient than CY 216 and the antithrombotic activity was mainly correlated to the anti-factor Xa activity. The ability of the 3 compounds to inhibit venous thrombosis growth was compared: they were found equipotent and the antithrombotic effect was independent of the anti-thrombin activity. The prohaemorrhagic properties were compared in the rabbit ear model. The activity of the 3 compounds were comparable and significantly less prohaemorrhagic than unfractionated heparin.(ABSTRACT TRUNCATED AT 250 WORDS)