Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).

No effect of norepinephrine dose on anti-Xa activity in critically ill patients
.

OBJECTIVE: Low-molecular-weight heparins are frequently used to prevent venous thromboembolism. Vasopressor therapy may be associated with inadequate anti-factor Xa activity, thereby increasing the risk of venous thromboembolism. We aimed to assess the association between anti-factor Xa activity and norepinephrine dose in intensive care unit (ICU) patients treated with subcutaneous dalteparin for venous thromboembolism prophylaxis. MATERIALS AND METHODS: This was a prospective observational pilot study in adult ICU patients treated with dalteparin 5,000 IU subcutaneously once daily and norepinephrine > 0.25 µg/kg/min. Peak anti-factor Xa activity was monitored and dalteparin doses were adjusted following a predefined dose algorithm. RESULTS: From November 2016 to April 2018, 32 patients were included. No correlation was found between norepinephrine dose and anti-factor Xa activity (r = -0.01, 95% confidence interval = -0.47 - 0.27, p = 0.57). Furthermore, following dalteparin 5,000 IU once daily, 28% of the patients showed anti-factor Xa activity < 0.10 IU/mL. Higher body mass index (BMI) (p < 0.001) but not patients' norepinephrine dose, age, or serum creatinine were risk factors for anti-factor Xa activity < 0.10 IU/mL. Dose increments to 7,500 IU once daily resulted in anti-factor Xa activity ≥ 0.10 IU/mL in all 5 patients (p = 0.043). CONCLUSION: In this cohort of ICU patients, no association was found between norepinephrine dose and anti-factor Xa activity following subcutaneous dalteparin 5,000-IU administration once daily. Furthermore, nearly one-third of the patients showed anti-factor Xa activity below the target concentration for venous thromboembolism prophylaxis. Higher BMI was an independent risk factor for reduced anti-Xa activity.

Pharmacodynamic properties and bioequivalence of dalteparin sodium subcutaneous injection in healthy Chinese male subjects.

1. Dalteparin sodium (DS) is a low molecular weight heparin that is widely used in the treatment of thromboembolism. The purpose of this study was to compare the pharmacodynamic properties and bioequivalence of the two formulations of DS with subcutaneous injection in healthy Chinese male subjects. 2. In this randomized, open-label, two-period crossover study, a total of 24 male subjects were recruited to receive single subcutaneous doses of test and reference DS injection in two different sequences (12 subjects each) with a seven-day washout period. Plasma samples were obtained at different time points after administration of the injection and measured by chromogenic substrate assay. The pharmacodynamic parameters including Emax, AUEC0-T, AUEC0-∞ and Tmax were analyzed to evaluate the bioequivalence of two DS formulations. 3. The relative bioequivalence was 107.7 ± 15.5 and 106.6 ± 29.8 for Anti-Xa and Anti-IIa, two major active metabolites of DS, respectively. The 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of Emax, AUEC0-T and AUEC0-∞ were 98.71-104.40%, 101.95-112.13% and 102.38-112.10% for Anti-Xa, and 100.88-110.42%, 95.76-112.62% and 92.24-111.32% for Anti-IIa, respectively, and all of the 90% CIs were within 80-125%. The T1/2 of reference and test were 2.88 ± 1.21 h and 2.76 ± 0.97 h for Anti-Xa, 1.87 ± 0.62 h and 1.96 ± 1.52 h for Anti-IIa. 4. Based on the pharmacodynamic parameters and FDA Guidance on DS and regulatory criteria for bioequivalence, the test and reference formulations were bioequivalent in healthy Chinese male subjects.

Assessment of the effects of dalteparin on coagulation variables and determination of a treatment schedule for use in cats.

OBJECTIVE To determine a treatment protocol for SC administration of dalteparin to cats on the basis of currently available detailed pharmacokinetic data and to assess the effect of SC administration of dalteparin to cats on coagulation variables such as activated partial thromboplastin time (aPTT), thrombin time, and results for thromboelastometry, compared with effects on anti-activated coagulation factor X (anti-Xa) activity. ANIMALS 6 healthy domestic shorthair cats. PROCEDURES Cats received 14 injections of dalteparin (75 anti-Xa U/kg, SC) at 6-hour intervals. Blood samples were collected before and 2 hours after the first and second injections on days 1, 2, and 4. Anti-Xa activity was measured by use of a chromogenic substrate assay, aPTT and thrombin time were measured by use of an automated coagulometer, and viscoelastic measurements were obtained with thromboelastrometry. RESULTS 2 hours after the second injection, the target peak anti-Xa activity range of 0.5 to 1.0 U/mL was achieved in all cats, whereas median trough values remained below this range. Peak anti-Xa activity had only minimal effects on coagulation variables; the maximum median ratio for aPTT (in relationship to the value before the first dalteparin injection) was 1.23. CONCLUSIONS AND CLINICAL RELEVANCE Results of this study indicated that this treatment protocol resulted in reproducible anti-Xa activity in cats that was mostly within the targeted peak range of anti-Xa activity recommended for humans. Treatment in accordance with this protocol may not require routine coagulation monitoring of cats, but this must be confirmed in feline patients.

A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment.

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Low-molecular-weight heparin pharmacokinetics: a dual absorption model approach.

OBJECTIVE: The aim of this study was to develop a novel population pharmacokinetic (PPK) model of dalteparin after subcutaneous (s.c.) injection, to describe the impact of the "flip-flop" phenomenon and to demonstrate any ethnic difference between Asian and Caucasian subjects. MATERIALS AND METHODS: The PPK model was constructed based on data collected from Asian (Japanese) and Caucasian (French) subjects with a total of 931 plasma anti-Xa activity measurements. After s.c. injection, the apparent elimination half-life of the dalteparin was about 4 hours, longer than that reported after intravenous (i.v.) injection, indicating a "flip-flop" phenomenon. In addition, following the mono-exponential decline profile after s.c. injection, a longer secondary phase was apparently observed in 70% of subjects. To investigate the phenomenon, we applied a dual absorption model including fast first-order and slow zero-order inputs as the structural model. RESULTS: The PPK model for s.c. injection provided the half-life consistent with that of i.v. injection and could account for the observed bi-phasic profile. Body weight and gender for clearance and body weight for volume of distribution were identified as covariates. Due to lower body weight in Asian subjects, an ethnic difference might occur but it would not be reflected by per kg body weight injection. CONCLUSIONS: Dalteparin PK profiles after s.c. injection were described reasonably by the novel PPK model based on flip-flop pharmacokinetics and a dual absorption process.

Pharmacokinetics of dalteparin during haemodialysis.

BACKGROUND/AIMS: Usually, the appropriate dosage of low-molecular-weight heparin during haemodialysis is empirically based on the clinical effect. We studied the pharmacokinetics of dalteparin during standard haemodialysis in different groups of patients to assess the added value of measuring the anti-Xa activity for dose monitoring and adjustments. METHODS: The pharmacokinetics of intravenously administered dalteparin during haemodialysis was studied in 9 patients during 27 haemodialysis sessions. Six patients received a single bolus dose of dalteparin (group 1), and 3 patients received a higher initial bolus dose of dalteparin followed by a second bolus dose after 2 h (group 2). The clinical effect was evaluated by visual inspection for clot formation in the extracorporeal circuit. RESULTS: The pharmacokinetic curve suggests a zero-order process of elimination. The mean decrease in anti-Xa activity (slope) was comparable in all patients. The mean anti-Xa activity at the end of haemodialysis (Clast) was 0.15 IU/ml in group 1 and 0.60 IU/ml in group 2. CONCLUSION: We conclude that measuring anti-Xa activity can be used to monitor the elimination of dalteparin during haemodialysis and is highly reproducible.

Tinzaparin versus dalteparin for periprocedure prophylaxis of thromboembolic events in hemodialysis patients: a randomized trial.

BACKGROUND: Low-molecular-weight heparin (LMWH) is cleared predominantly by the kidneys and hence there is uncertainty about the safety of its use in hemodialysis (HD) patients. Our primary objective was to compare whether tinzaparin and dalteparin differentially accumulate in HD patients. STUDY DESIGN: Open-label randomized controlled trial. SETTING & PARTICIPANTS: HD patients undergoing periprocedure bridging anticoagulation. INTERVENTION: After warfarin therapy was discontinued, participants were randomly assigned to either 3 daily doses of tinzaparin (175 IU/kg) or dalteparin (200 IU/kg), with 2 intervening HD treatments between the first dose of study drug and their procedure. OUTCOMES: The primary outcome was predialysis anti-Xa levels 20 to 24 hours after the third LMWH dose (therapeutic target, <0.2 IU/mL). Secondary outcomes included thromboembolic events and major bleeding. RESULTS: Of 29 eligible and consenting patients, 17 patients received tinzaparin and 12 patients received dalteparin. Mean predialysis anti-Xa level 20-24 hours after the third LMWH dose was 0.37 ± 0.23 (SD) IU/mL for tinzaparin and 0.62 ± 0.41 IU/mL for dalteparin (P = 0.1), indicating clinically important accumulation for both drugs. No invasive procedures were canceled due to study drug accumulation. 4 patients experienced serious adverse events (1 major bleed after traumatic arteriovenous fistula puncture in the tinzaparin arm, 2 non-ST-elevation myocardial infarctions [1 in each group], and 1 upper-extremity deep venous thrombosis [dalteparin group]). LIMITATIONS: Small sample size. CONCLUSIONS: Dalteparin and tinzaparin significantly accumulate in HD patients at therapeutic doses. "Bridging therapy" with LMWHs at therapeutic doses in HD patients who require temporary interruption of warfarin therapy has the potential for complications and is of uncertain benefit. Other anticoagulation strategies, including no bridging therapy or intravenous heparin, need comparative evaluation in this unique patient population.

Pharmacokinetics of the low molecular weight heparin dalteparin in cats.

Low molecular weight heparin (LMWH) is used as an anticoagulant in cats although only limited pharmacokinetic data are available in this species. The aim of the present study was to establish the pharmacokinetics of dalteparin in cats based on anti-FXa heparin activities. Groups of clinically healthy cats (six animals per treatment) received individual LMWH injections at three different doses intravenously (IV) (25, 50, 100 anti-factor Xa international units [IU anti-FXa]/kg) or subcutaneously (SC) (50, 100, 200 IU anti-FXa/kg). Blood samples were collected before and at various times after injection. Anti-FXa activity was measured with a chromogenic substrate test. Following IV injection, maximum plasma heparin activities (C(max)) were 0.67 ± 0.14, 1.44 ± 0.22 and 2.87 ± 0.38 IU anti-FXa/mL, respectively. The calculated mean half-life (t(½)) was between 39 and 57 min and was not significantly dose-dependent (P=0.139). The volume of distribution (35-39 mL/kg) was almost equivalent to the plasma volume. After SC injection, C(max) values of 0.41 ± 0.10, 0.86 ± 0.17 or 1.91 ± 0.16 IU anti-FXa/mL, respectively, were calculated at 91-110 min post-injection. The t(½) values were between 106 and 122 min and were not significantly influenced by dose (P=0.784). The bioavailability after SC injection was approximately 100%. The high bioavailability of the SC administered LMWH dalteparin in cats was consistent with other species and indicated predictable blood levels. However, the comparatively short t(½) may indicate the necessity of multiple daily injections, which should be verified in clinical trials.

[Administration of dalteparin in reconstructive vascular surgery].

The article contains a review of the literature regarding the use of low-molecular-weight heparins (LMWHs) exemplified by dalteparin in the hitherto insufficiently explored area of their implementation, i. e., during the intraoperative period in patients suff ering from atherothrombosis. Presented herein is analysis of alterations in the parameters of the plasmatic and thrombocytic links of haemostatis during intraoperative administration of various molecular-weight fractions of heparin. The obtained findings make it possible to conclude that LMWHs do off er certain advantages when used during surgical interventions in patients with atherosclerotic lesions of the arterial bed.

Comparison of a direct Factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: a randomised controlled trial in healthy elderly adults.

INTRODUCTION: Edoxaban (the free base of DU-176b) is a new, oral direct Factor Xa inhibitor. This is the first study to compare the hemostatic response to edoxaban, ximelagatran, and dalteparin in healthy, elderly adults. MATERIALS AND METHODS: In this open-label, active-controlled clinical trial, 40 adults (65-75 years), were randomised to: oral edoxaban (60 mg, twice-daily, 7 doses), subcutaneous dalteparin (5000 IU, once-daily, 4 doses), oral ximelagatran (24 mg, twice-daily, 7 doses) or no drug. Blood samples were taken before, and 1.5, 4, 12, 24, 72, 84, 96, 108, 120, and 144 hours after, the first dose. The primary outcomes were changes in thrombin-antithrombin complex, prothrombin fragment 1+2 and D-dimer, and adverse events. Additional biomarkers of coagulation, and endothelial cell and platelet activation were compared (ANOVA). RESULTS: All subjects completed the study. Inhibition of thrombin generation lag time, peak, and constant velocity index were significantly greater, and extended for a longer period of time, following edoxaban administration, compared with dalteparin. We found that the traditional assay for anti-FXa activity was not appropriate for the new anticoagulants. Biomarker changes following edoxaban administration (including prolongation of prothrombin time) reflected inhibition of Factor Xa; there was no effect on platelet, tissue factor or endothelial activation. There were no clinically significant changes in primary outcomes. No serious adverse events were reported. CONCLUSION: Oral administration of edoxaban resulted in effective Factor Xa and TG inhibition, and was well-tolerated. Studies are needed to confirm edoxaban (60 mg daily) use in clinical practice. SPONSORSHIP: Daiichi Sankyo Pharma Development.

Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insufficiency.

BACKGROUND: Low-molecular-weight heparins (LMWH) are effective, safe and convenient for anticoagulation. Their use is limited in patients with renal insufficiency (RI) because of bioaccumulation. OBJECTIVES: Evaluate pharmacokinetic data of dalteparin at a therapeutic dose in patients with RI. PATIENTS AND METHODS: Prospective observational cohort study. Inpatients were included into three groups according to glomerular filtration rate (GFR): A > or = 60, B 30-59, C < 30 mL min(-1) 1.73 m(-2). Dalteparin was injected subcutaneously (s.c.) twice daily. Peak plasma anti-factor Xa activity (anti-Xa) was measured and adjusted to applied dose and body weight after the first dose, on day 2, and every 2nd day afterwards. Bioaccumulation factor R was calculated as quotient of the last and the first adjusted anti-Xa. Data are shown as median (interquartile range, IQR). RESULTS: Thirty-two patients (23 men) receiving dalteparin for > or = 2 days were analyzed. Follow-up was 6 days (IQR 4-10, range 2-22). Median dose was 90 (73-106) units kg(-1) per 12 h (P = 0.68). After the first dose, adjusted anti-Xa levels were 3.5 (2.6-5.0), 4.8 (3.3-5.5), 4.5 (3.7-7.5) x 10(-3) for the groups A, B, C; P = 0.26. On the last day, they were 6.1 (3.7-7.3), 7.1 (5.6-8.3), 10.2 (7.8-13.2) x 10(-3); A compared with C, P = 0.002. R was 1.46 (1.15-1.82), 1.36 (1.20-2.16) and 2.28 (1.53-2.93); A compared with C, P = 0.18. CONCLUSION: Therapeutically dosed dalteparin accumulates in patients with severe RI (group C). Dose adjustments according to anti-Xa are recommended for dalteparin if used in this patient population. However, no simple dosing scheme can be suggested yet because of wide inter-individual variation.

Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function.

BACKGROUND: Low-molecular-weight heparins (LMWH) have been shown to be effective and safe for prophylaxis of thromboembolic diseases. However, issues regarding safety and optimal use of LMWH arise in patients with renal insufficiency (RI). OBJECTIVES: To compare pharmacokinetic data of dalteparin for up to 3 weeks in patients with various degrees of RI. PATIENTS AND METHODS: Patients from general medical and surgical wards were included in this prospective cohort study and divided into three groups according to renal function: A=normal (GFR>or=60 mL min(-1)1.73 m(-2)), B=mild RI (GFR 30-59 mL min(-1)1.73 m(-2)), C=severe RI (GFR<30 mL min(-1)1.73 m(-2)). Dalteparin was injected s.c. once daily at a prophylactic dose. Peak anti-Xa activity levels (anti-Xa) were measured 4+/-1 h after injection on day 1 and every third day up to 3 weeks. Primary objectives were peak anti-Xa levels and adjusted anti-Xa levels, adjustment being carried out for dose and body weight. RESULTS: A total of 42 patients could be analyzed during a median of 10 days (interquartile range IQR 4-13, range 1-20). In all groups, adjusted peak anti-Xa levels were not different on day 10 compared with day 1. No bioaccumulation>30% could be found up to day 10 even in patients with severe RI. CONCLUSION: The use of dalteparin at a prophylactic dose was not associated with a bioaccumulation>30% even in patients with severe renal insufficiency during a median follow-up of 10 days (IQR 4-13, range 1-20).

Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study.

BACKGROUND: Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency. METHODS: We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17. RESULTS: We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower. CONCLUSION: In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00138099.

Management of venous thromboembolism in patients with cancer: role of dalteparin.

Cancer is a major risk factor for the development of venous thromboembolism (VTE). Conventional anticoagulant therapy with a vitamin K antagonist is more problematic in cancer patients due to an increased risk of recurrent VTE, and an increased risk of anticoagulant-related bleeding. In recent years, there has been a shift toward treating cancer patients with VTE with extended duration dalteparin. Dalteparin, a low-molecular-weight heparin, has been shown to be more effective, and as safe as conventional anticoagulant therapy, in cancer patients with VTE. This paper will (a) review the relationship between cancer and VTE, and (b) provide an overview of the role of dalteparin in the management of VTE in patients with cancer.

Xa inhibition and coagulation activity--the influence of prolonged dalteparin treatment and gender in patients with acute coronary syndrome and healthy individuals.

BACKGROUND: We evaluated coagulation activity in relation to gender in patients with acute coronary syndromes and in healthy individuals of similar age, and related coagulation activity to levels of Xa inhibition during dalteparin treatment. METHODS: Serial blood samples were obtained from 555 (172 women) of 2267 patients in the Scandinavian FRISC II study, and a single sample in 457 (151 women) apparently healthy age- and sex-matched individuals. After randomization, all patients received dalteparin 120 IU/kg s.c. (maximum 10,000 IU) twice daily for 5 to 7 days inhospital and thereafter placebo (n = 285) or sex- and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months. RESULTS: Before randomization, 96% of the patients had open-label anticoagulation with unfractionated heparin or dalteparin. Therapeutic anti-Xa levels (> 0.5 IU/mL) were found in 74%, 55%, 58%, and 33% of the dalteparin-treated patients at randomization, 2 days, 4 to 7 weeks, and 3 months, respectively, and were significantly related to lower levels of coagulation activity, ie, factor VIIa, prothrombin fragment 1+2, and D-dimer, during prolonged treatment. Female patients had higher anti-Xa levels than men at randomization (median 0.69 vs 0.60 IU/mL, P = .01) and at 2 days (0.65 vs 0.59 IU/mL, P < .001). Female patients had also significantly higher levels of all 3 coagulation markers at randomization, 2 days, 4 to 7 weeks, and 3 and 6 months. Similarly, healthy women had higher prothrombin fragment 1+2 levels (median 1.19 vs 0.94 nmol/L) and D-dimer levels than men (26 vs 21 microg/L) (both P < .001). CONCLUSIONS: Despite weight-adjusted dosing, female patients reached higher anti-Xa levels, suggesting increased sensitivity to dalteparin treatment. Healthy women and female patients also had higher coagulation activity, which might increase the risk of thrombus formation. The large proportion of patients with subtherapeutic anti-Xa during prolonged dalteparin treatment may reflect poor compliance and could thus contribute to the gradual loss of clinical efficacy.

A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients.

Low-molecular-weight heparins undergo renal elimination, and therefore the proper dosing in hemodialysis (HD) patients is unclear. It was the objective of this study to evaluate the pharmacokinetic (PK) parameters of dalteparin in patients receiving chronic HD for end-stage renal disease. We performed a multidose PK study with prophylactic doses of dalteparin in twelve HD patients. Dalteparin 5,000 IU was administered subcutaneously daily for four consecutive days, with HD performed on day 2 and day 4. Anti-factor Xa activity was determined daily and at multiple blood samples after the 3rd and 4th dose. Eleven of 12 patients completed the study. The mean (range) PK parameters determined after the 4th dose were as follows: i) maximum concentration (Cmax ) was 0.31 IU/ml (0.06 to 0.55 IU/ml); ii) time to Cmax was 3.55 hours (2.59 to 4.96 hr); iii) area under the curve was 3.24 IU*hr/ml (0.64 to 6.44 IU*hr/ml); iv) half-life was 3.82 hr (2.03 to 9.63 hr); and v) trough anti-factor Xa activity 0.04 IU/ml (0.02 to 0.08 IU/ml). No major bleeding was observed. In general, patients with lower body weight exhibited a higher Cmax . From this pilot PK study, we have determined initial PK parameters for dalteparin in HD patients. Although a standard prophylactic dose was used, we found that in this patient population differences in body weight influenced the Cmax. Future studies to evaluate the PK parameters of dalteparin in patients receiving chronic HD may have to use weight-based dosing and will need to be performed over a longer period of time.

Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency.

The pharmacokinetics of the low-molecular weight heparin (LMWH), dalteparin, was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers, 8 patients with moderate/severe renal failure (Cl(crea) 13.1-56.5 ml/min) and 8 hemodialysis patients. Venous blood samples were taken over a 1-day period to determine anti-Xa activity, anti-IIa activity and plasma levels of free tissue factor pathway inhibitor (free TFPI). Plasma anti-Xa and anti-IIa activities were measured using chromogenic assays and free TFPI levels using an ELISA technique. The anti-Xa clearance was significantly decreased (p < 0.05) in both groups with renal insufficiency when compared with healthy volunteers. There was a positive correlation between creatinine clearance and anti-Xa clearance in the healthy volunteers and patients with moderate/severe renal failure. The anti-Ila activity was characterized by 3- to 4-fold lower plasma concentrations and faster elimination compared with the anti-Xa activity. In patients with moderate/severe renal failure the elimination of anti-lla was only slightly decreased, whereas in hemodialysis patients anti-Ila clearance was significantly decreased (p < 0.01). There was no correlation between creatinine clearance and anti-IIa clearance. The baseline mean free TFPI plasma levels in the two groups with renal insufficiency were significantly higher (p < 0.01) than in healthy volunteers. Dalteparin administration induced a transient, 6.0- to 8.1-fold increase in the free TFPI values in the three study groups. Dalteparin induced an increase in C(max) and AUC(0 - infinity) values of free TFPI in the two groups with renal insufficiency that was higher than in healthy volunteers. No bleeding complications occurred during the study. In conclusion, this is the first report showing retarded elimination of dalteparin and enhanced free TFPI plasma levels induced by a LMWH in patients with renal insufficiency.

Safety of dalteparin for the prophylaxis of venous thromboembolism in elderly medical patients with renal insufficiency: a pilot study.

The aim of this prospective cohort study was to determine the incidence of dalteparin bioaccumulation (measured using anti-Xa levels), and bleeding during thromboprophylaxis in elderly patients with renal failure who were admitted to hospital with an acute medical illness. Patients who met the criteria for being at high thromboembolic risk received dalteparin 5,000 IU subcutaneously once daily while the other patients (low risk) received 2,500 IU daily. Thromboprophylaxis was administered for at least 6 days. Anti-Xa activity was determined before the first dalteparin dose and again on day 6, 4 hours after the administration of the dalteparin dose. Bleeding was assessed daily. Compression ultrasonography was performed to identify any deep vein thromboses. There was no evidence of bioaccumulation on day 6 of therapy, irrespective of renal function. No episodes of major bleeding or venous thromboembolism occurred. Larger, randomized studies are warranted to confirm the safety of dalteparin in this patient population.