Venous thromboembolism in burns patients: Are we underestimating the risk and underdosing our prophylaxis?

BACKGROUND: Burns patients exhibit all factors of Virchow's triad and are thus at high theoretical risk of venous thromboembolism (VTE). At our tertiary referral burns unit, a standard dose of low molecular weight heparin, which acts primarily by inhibiting Factor Xa, is given for thromboprophylaxis. However, the pharmacokinetics of enoxaparin are altered following a burn injury, and thus burns patients are likely underdosed on their thromboprophylaxis. The objectives of this study were to determine the incidence and risk factors for VTE among burns patients at the Victorian Adult Burns Service (VABS) and to determine the adequacy of the current enoxaparin thromboprophylaxis regimen through measurement of anti-factor Xa (AFXa) levels and comparison with established reference ranges. METHODS: This study consisted of two parts. In part 1, the Burns Registry of Australia and New Zealand (BRANZ) was reviewed for cases of VTE in burns patients admitted to the VABS from 2013 - 2018. Part 2 was a prospective study that determined peak and trough AFXa levels in patients admitted to the VABS with >10% total body surface area (TBSA) burns. RESULTS: Part 1. Totally, 1,475 patients were admitted to the VABS between 2013 - 2018. There were 20 cases of VTE (1.36%). Percent TBSA of burn (OR = 1.04, 95% CI: 1.03 - 1.06), full thickness burns (OR = 2.78, 95% CI: 1.15 - 6.73), ICU admission (OR = 15.08, 95% CI: 5.01 - 45.44), mechanical ventilation (OR = 10.62, 95% CI: 4.05 - 27.91), operative procedures (OR = 1.43, 95% CI: 1.29 - 1.59), and a longer hospital stay (OR = 1.05, 95% CI: 1.04 - 1.07) were all associated with an increased VTE risk. Part 2. A total of 20 participants with >10% TBSA burns were recruited to the prospective study. Peak anti Factor Xa (AFXa) levels were measured for all 20 participants with 15% recording an initial prophylactic peak AFXa level within reference range. Upon subsequent measurements, 50% of participants reached a prophylactic peak AFXa level. Trough AFXa levels were measured for 17 participants with no participant recording an initial or subsequent trough AFXa level at or above the prophylactic threshold. CONCLUSION: Our study demonstrates a high incidence of VTE among burns patients at the VABS, especially among the major burns patients, and a thromboprophylaxis protocol that is ineffective in achieving prophylactic levels of AFXa level. The evidence suggests a need to evaluate different dosing protocols among burns patients in order to improve AFXa levels, with the aim of decreasing incidence of VTE in high-risk patients.

Rethinking the one-size-fits-most approach to venous thromboembolism prophylaxis after radical cystectomy.

OBJECTIVES: Empirically dosed enoxaparin is routinely given in the postoperative period for venous thromboembolism (VTE) prophylaxis after radical cystectomy (RC). Patient-specific factors may alter its pharmacokinetics, and it is unclear whether this leads to levels sufficient for antithrombosis. We sought to evaluate variability of anti-factor Xa levels in a cohort of RC patients receiving perioperative enoxaparin prophylaxis. MATERIAL AND METHODS: Patients undergoing RC at a single institution were placed on a postoperative pathway that included enoxaparin. An anti-factor Xa level was drawn 2 to 4 hours after the third dose. The target range for prophylaxis was 0.3 IU/ml to 0.5 IU/ml. RESULTS: The primary outcome was anti-factor Xa level. Demographics, operative time, hospital course, and 30-days post-operative VTE were compared by anti-factor Xa level group using univariate and multivariable analyses. Between January 2018 and 2019, 107 RC patients remained on pathway and were included in our analysis. Sixty-five (61%) were below target range for VTE prophylaxis.  A single VTE event (0.9%) occurred in a subprophylactic individual. The subprophylactic group had a significantly higher body mass index (P < 0.01) than those within target range. CONCLUSIONS: Higher body mass index was associated with subprophylactic enoxaparin dosing after RC. Nearly two-thirds of patients had below target anti-factor Xa levels. This suggests that dosing could be further individualized, but given the low incidence of VTE, implications of dose-adjusted prophylaxis on VTE prevention remain unknown.

Circulating heparan sulfate chains and body weight contribute to anti-Xa levels in cancer patients using the prophylactic dose of enoxaparin.

Hospitalized cancer patients are at increased risk of thrombosis and prophylaxis with heparin is recommended. Heparanase is a protein capable of degrading heparan sulfate (HS) chains. The first objective of the study was to examine the effects of weight on anti-Xa levels in cancer patients treated with a fixed dose of enoxaparin as thromboprophylaxis. The second aim was to assess a potential correlation between plasma pre-treatment coagulation parameters and anti-Xa levels in an assumption that heparanase degradation activity towards heparins and HS chains could affect anti-Xa levels. Two blood samples (prior to and 3 h after drug injection) of 76 cancer patients with an indication for prophylaxis with enoxaparin (40 mg) were evaluated for coagulation markers. Sub-prophylactic levels of anti-Xa (< 0.2 U/ml) were found in 16/76 (21%) patients; in 13/76 (13%) patients the values were supra-prophylactic (> 0.5 U/ml). In the subgroup of patients weighing > 80 kg, 7/14 (50%) individuals had a sub-prophylactic level. Overall, anti-Xa levels appeared to correlate with patient's weight (r = - 0.48, p < 0.0001), pre-treatment partial thromboplastin time (PTT), D-dimer, HS, heparanase levels and procoagulant activity. We concluded that plasma anti-Xa levels correlated with patient's weight. A substantial portion of cancer patients receiving enoxaparin prophylaxis was undertreated. For patients > 80 kg, a weight-adjusted prophylactic dose of enoxaparin could be considered. Elevated enoxaparin anti-Xa levels correlated with pre-treatment parameters of coagulation system activation. High pre-treatment HS and elevated plasma anti-Xa levels may potentially serve as biomarkers for the identification of patients at increased thrombosis risk.

Safety and Pharmacokinetics of DS-1040 Drug-Drug Interactions With Aspirin, Clopidogrel, and Enoxaparin.

DS-1040, a novel low-molecular-weight inhibitor of activated thrombin-activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS-1040 along with the effect on DS-1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single-dose DS-1040 with multiple-dose aspirin, multiple-dose clopidogrel, or single-dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding-related TEAEs, and no significant changes in coagulation parameters. DS-1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS-1040 PK was evaluated following the concomitant administration with multiple-dose aspirin, where the plasma DS-1040 exposure (peak plasma concentration [Cmax ] and area under the concentration-time curve [AUCinf ]) was to be similar to the data previously published in the first-in-human study of DS-1040 in healthy subjects. The PK parameters of DS-1040 coadministered with clopidogrel were similar to those of DS-1040 alone, with small increases in geometric means for Cmax (7%) and AUClast (9%). When coadministered with enoxaparin, the PK parameters of DS-1040 were not affected (1.1% and 1.5% decreases in geometric means for Cmax and AUClast , respectively). Therefore, concomitant administration of DS-1040 and clopidogrel or enoxaparin did not demonstrate PK drug-drug interactions.

Permeation-Enhancing Nanoparticle Formulation to Enable Oral Absorption of Enoxaparin.

This study tests the hypothesis that association complexes formed between enoxaparin and cetyltrimethylammonium bromide (CTAB) augment permeation across the gastrointestinal mucosa due to improved encapsulation of this hydrophilic macromolecule within biocompatible poly (lactide-co-glycolide, PLGA RG 503) nanoparticles. When compared with free enoxaparin, association with CTAB increased drug encapsulation efficiency within PLGA nanoparticles from 40.3 ± 3.4 to 99.1 ± 1.0%. Drug release from enoxaparin/CTAB PLGA nanoparticles was assessed in HBSS, pH 7.4 and FASSIFV2, pH 6.5, suggesting effective protection of PLGA-encapsulated enoxaparin from unfavorable intestinal conditions. The stability of the enoxaparin/CTAB ion pair complex was pH-dependent, resulting in more rapid dissociation under simulated plasma conditions (i.e., pH 7.4) than in the presence of a mild acidic gastrointestinal environment (i.e., pH 6.5). The intestinal flux of enoxaparin complexes across in vitro Caco-2 cell monolayers was greater when encapsulated within PLGA nanoparticles. Limited changes in transepithelial transport of PLGA-encapsulated enoxaparin complexes in the presence of increasing CTAB concentrations suggest a significant contribution of size-dependent passive diffusion as the predominant transport mechanism facilitating intestinal absorption. Graphical abstract.

Fixed or Weight-Tiered Enoxaparin After Thoracic Surgery for Venous Thromboembolism Prevention.

BACKGROUND: Venous thromboembolism is an important patient safety issue in thoracic surgery patients. The optimal enoxaparin dose remains unclear. This multicenter pre/post clinical trial compared the pharmacokinetics of fixed versus weight-tiered enoxaparin, and their impact on 90-day venous thromboembolism and bleeding. METHODS: Thoracic surgery patients were prospectively enrolled using a pre/post study design. Cohort 1 received enoxaparin 40 mg daily, and cohort 2 received a weight-tiered regimen: less than 70 kg received 30 mg daily; 70 kg to 89.9 kg received 40 mg once daily; and 90 kg or more received 50 mg daily. The primary study outcome was peak anti-factor Xa levels in response to fixed or weight-tiered enoxaparin. Secondary outcomes included trough anti-factor Xa, 90-day symptomatic venous thromboembolism, and 90-day clinically relevant bleeding. RESULTS: One hundred thirty-one patients were prospectively enrolled, including 65 in the fixed-dose cohort and 66 in the weight-tiered cohort. No patient was lost to follow-up. Weight-tiered enoxaparin was not significantly more likely to produce adequate anticoagulation (peak anti-factor Xa 0.3 IU/mL or greater) when compared with fixed-dose enoxaparin (44.3% vs 48.2%, P = .67). Weight-tiered enoxaparin was not more likely to avoid over-anticoagulation (peak anti-factor Xa 0.5 IU/mL or greater) when compared with fixed-dose enoxaparin (3.3% vs 3.6%, P = 1.00). The groups had no significant difference in trough anti-factor Xa. Observed rates of 90-day symptomatic venous thromboembolism and clinically relevant bleeding were low (0% and 3.1%, respectively) and were not significantly different between groups. CONCLUSIONS: This multicenter pre/post clinical trial did not show a pharmacokinetic advantage to weight-tiered enoxaparin, when compared with fixed-dose enoxaparin, in thoracic surgery patients. (Clinicaltrials.gov identifier: NCT03251963.).

Prophylactic Use of Enoxaparin in Adolescents During Bariatric Surgery-a Prospective Clinical Study.

INTRODUCTION: Severe obesity predisposes youth to a higher risk of venous thromboembolism (VTE). This study evaluates a BMI-stratified prophylactic dosing regimen of enoxaparin in adolescents with severe obesity undergoing surgery. METHODS: Adolescents aged 12-20 years received prophylactic enoxaparin at 40 mg SC (for a BMI < 50 kg/m2) and 60 mg SC (for a BMI ≥ 50 kg/m2) every 12 h until discharge. Blood samples were drawn at pre-dose, 1, 2, 4, 6, and 12 h. Plasma Anti-Factor Xa (Anti-FXa) activity was used as a surrogate marker for enoxaparin pharmacokinetics. RESULTS: Ten female and two male obese adolescents (age range 14-19 years) had a mean BMI of 49.9 kg/m2 (38.4-58 kg/m2). Four patients had a BMI of less than 50 kg/m2 and received 40 mg enoxaparin, resulting in a mean dosage of 0.352 ± 0.070 mg/kg body weight. Eight patients were dosed with 60 mg enoxaparin every 12 h, resulting in a mean dosage of 0.395 ± 0.028 mg/kg. Peak plasma anti-FXa activity (Cmax) ranged from 0.14 to 0.30 IU/mL, median Cmax was 0.205 IU/mL. Median Tmax was 5.67 h (range 3.78-7.52 h). Median AUCi was 1.00 h IU/mL (range 0.42-1.67 h IU/mL). Ten out of 12 patients (83%) reached the primary endpoint with anti-FXa activity in the range for VTE prevention (0.1-0.3 IU/mL). CONCLUSIONS: Our dosing scheme of 40 mg vs. 60 mg enoxaparin stratified according to BMI proved to be effective in reaching prophylactic anti-FXa activity in 83% of adolescent patients.

Assessment of Anti-Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics.

Importance: Between 4% and 12% of patients undergoing colorectal surgery and receiving enoxaparin, 40 mg per day, have a postoperative venous thromboembolism (VTE) event. An improved understanding of why "breakthrough" VTE events occur despite guideline-compliant prophylaxis is an important patient safety question. Objective: To determine the proportion of patients undergoing colorectal surgery who received adequate anticoagulation based on peak anti-factor Xa (aFXa) levels while receiving enoxaparin at 40 mg per day. Design, Setting, and Participants: This prospective, nonrandomized clinical trial was conducted between February 2017 and July 2018 with 90-day follow-up at a quaternary academic medical center in the Intermountain West and included patients undergoing colorectal surgery who had surgery after receiving general anesthesia, were admitted for at least 3 days, and received enoxaparin, 40 mg once daily. Interventions: All patients had aFXa levels measured after receiving enoxaparin 40 mg per day. Patients whose aFXa level was out of range entered the trial's interventional arm where real-time enoxaparin dose adjustment and repeated aFXa measurement were performed. Main Outcomes and Measures: Primary outcome: in-range peak aFXa levels (goal range, 0.3-0.5 IU/mL) with enoxaparin, 40 mg per day. Secondary outcomes: (1) in-range trough aFXa levels (goal range, 0.1-0.2 IU/mL) and (2) the proportion of patients with in-range peak aFXa levels from enoxaparin, 40 mg once daily, vs the real-time enoxaparin dose adjustment protocol. Results: Over 16 months, 116 patients undergoing colorectal surgery (65 women [56.0%]; 99 white individuals [85.3%], 13 Hispanic or Latino individuals [11.2%], and 4 Pacific Islander individuals [3.5%]; mean [range] age, 52.1 [18-85] years) were enrolled. Among 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation (aFXa < 0.3 IU/mL) with enoxaparin, 40 mg per day. Weight and peak aFXa levels were inversely correlated (r2 = 0.38). Forty-seven patients (77%) had a trough aFXa level that was not detectable (ie, most patients had no detectable level of anticoagulation for at least 12 hours per day). Real-time enoxaparin dose adjustment was effective. Patients were significantly more likely to achieve an in-range peak aFXa with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001). Conclusions and Relevance: This study supports the finding that most patients undergoing colorectal surgery receive inadequate prophylaxis from enoxaparin, 40 mg once daily. These findings may explain the high rate of "breakthrough" VTE observed in many clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT02704052.

An in vitro study to investigate the interference of enoxaparin on plasma levels of direct oral factor Xa inhibitors measured by chromogenic assays.

INTRODUCTION: Co-administration of enoxaparin and a direct oral factor Xa inhibitor (xabans: apixaban, edoxaban, rivaroxaban) could give rise to the problem of overlapping the anti-Xa activity when measuring direct oral anticoagulant (DOAC) levels. We aimed to evaluate in vitro the degree of the interference of increasing enoxaparin concentrations on xaban plasma levels measured by different chromogenic anti-Xa assays with drug-specific calibrators and controls. METHODS: Seven plasma samples were spiked with apixaban, edoxaban, or rivaroxaban at fixed concentration, and enoxaparin at increasing concentrations (0, 0.125, 0.250, 0.50, 1.0, 1.50, and 2.0 IU/mL). The evaluated chromogenic assays were as follows: Biophen DiXaI and Biophen Heparin LRT (Hyphen BioMed), Berichrom Heparin and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). RESULTS: The presence of enoxaparin caused increased DOAC levels, with over-estimation depending on the anti-Xa assay and on the heparin concentration in the sample. The smallest over-estimation was in the sample with enoxaparin 0.125 IU/mL and the greatest in the sample with enoxaparin 2.0 IU/mL (0%, 3.1%, and 7.4% vs 583.8%, 526.1%, and 415.2% for apixaban, edoxaban, and rivaroxaban, respectively). Biophen DiXaI showed lower interference compared to other methods (maximum over-estimation in the presence of enoxaparin 2.0 IU/mL: 56.4% dosing rivaroxaban by Biophen DIXaI vs 583.8% dosing apixaban by Berichrom Heparin). CONCLUSION: The presence of enoxaparin interferes with xabans measurement by chromogenic anti-Xa assays causing falsely elevated DOAC levels, the over-estimation being dependent on the anti-Xa assay and on the heparin concentration in the sample.

Pharmacokinetics of Enoxaparin After Renal Transplantation in Pediatric Patients.

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off-label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti-Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti-Xa activity 36 hours after initiation of treatment, (2) anti-Xa time courses were best described by a 1-compartment open model with first-order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between-subject and between-occasion variabilities in anti-Xa activity were observed. However, creatinine-based estimated glomerular filtration rate in the first post-renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian-based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti-Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti-Xa activity (targeting 0.3-0.5 IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units.

Comparative Pharmacokinetic Profile of 3 Batches of Ovine Low-Molecular-Weight Heparin and 1 Batch of Branded Enoxaparin.

Although pharmaceutical grade heparin is obtained almost exclusively from porcine intestinal mucosa, there is interest in diversifying heparin sourcing to address potential supply shortages and economically motivated adulteration. Since ovine-derived heparin is structurally similar to porcine heparin, it is expected that ovine-derived low-molecular-weight heparin (LMWH) will be comparable to porcine-derived LMWH. This study compared the pharmacokinetic (PK) behavior of 3 batches of ovine LMWH with that of enoxaparin in nonhuman primates. Blood samples were collected prior to and at 2, 4, and 6 hours post-administration of a 1 mg/kg subcutaneous dose of LMWH. Circulating drug concentrations determined using anti-Xa and anti-thrombin assays were used to calculate values for PK parameters. Tissue factor pathway inhibitor (TFPI) levels were measured by enzyme-linked immunosorbent assay. The ovine LMWHs tested met pharmacopoeial potency and molecular weight distribution requirements for enoxaparin. In the post-administration samples, comparable levels of branded enoxaparin and ovine enoxaparin were observed using anti-Xa and anti-thrombin assays, with the concentration versus time curves being nearly superimposable. Consistent with this similarity, no significant differences were observed between PK parameters calculated for branded enoxaparin and ovine LMWH. The TFPI levels returned to baseline levels by 6 hours in ovine LMWH-treated animals but remained slightly elevated in animals treated with branded enoxaparin. It is concluded that the pharmacokinetics of ovine enoxaparin were not only comparable between different batches but also similar to the branded product. Thus, LMWH prepared from ovine mucosal heparin is comparable to its porcine-derived counterpart.

Increased Enoxaparin Dosing Requirements for Treatment of Deep Vein Thrombosis in a Severely Burned Patient: Case Report and Literature Review.

Dosing of enoxaparin for deep vein thrombosis (DVT) prophylaxis in acutely burned patients has been shown to result in anti-Xa levels below target range. We describe the first case report, to our knowledge, of a severely burned patient who, despite prophylactic dosing of enoxaparin 30 mg subcutaneously twice daily, developed an acute DVT that required high-dose enoxaparin (100 mg [1.5 mg/kg] subcutaneously every 8 hours) to maintain anti-Xa levels within the therapeutic range (0.6-1 IU/ml). Pharmacokinetic evaluations were performed using anti-Xa levels measured throughout the patient's hospital stay to validate the appropriateness of this high-dose regimen based on established therapeutic anti-Xa level ranges. These results suggest that routine anti-Xa level monitoring, regardless of enoxaparin dosing, is necessary for burn patients who are receiving enoxaparin given their hypermetabolic state following injury.

Enoxaparin 40 mg per Day Is Inadequate for Venous Thromboembolism Prophylaxis After Thoracic Surgical Procedure.

BACKGROUND: Many patients undergoing thoracic surgical procedures have venous thromboembolism (VTE) events despite the receipt of chemical prophylaxis. Enoxaparin's pharmacologic impact can be quantified by using anti-Factor Xa (aFXa) levels. We hypothesized that enoxaparin 40 mg once daily would be inadequate for most inpatients undergoing thoracic surgical procedures and that a real-time dose adjustment algorithm would be effective. METHODS: This prospective clinical trial enrolled inpatients who were to undergo a thoracic surgical procedure and placed on enoxaparin 40 mg once daily for VTE prophylaxis after surgical procedures. aFXa levels were used to measure the anticoagulant effect of enoxaparin once steady state had been reached. Patients whose aFXa levels were out of range received real-time enoxaparin dose adjustment and had repeat aFXa levels drawn. RESULTS: Ninety-three inpatients undergoing thoracic surgical procedures were prospectively enrolled. The majority of patients (67.4%) had low peak aFXa levels (<0.3 IU/mL), indicative of inadequate enoxaparin prophylaxis, and 30.3% of patients had in-range aFXa levels (0.3 to 0.5 IU/mL). Patient weight had a moderate correlation (r2 0.38) with peak aFXa level. Patient weight, female sex, and preoperative creatinine were independent predictors of peak aFXa in a linear regression model. Real-time, protocol-driven enoxaparin dose adjustment allowed a significantly increased proportion of patients to achieve in-range aFXa levels (30.3% vs 97.6%, p < 0.001). CONCLUSIONS: Enoxaparin 40 mg once daily is inadequate for most inpatients undergoing thoracic surgical procedures, based on a pharmacodynamic study of aFXa levels. Future research should examine the impact of weight-based once daily enoxaparin dosing versus twice daily enoxaparin dosing on prophylaxis adequacy.

Twice-Daily Enoxaparin among Plastic Surgery Inpatients: An Examination of Pharmacodynamics, 90-Day Venous Thromboembolism, and 90-Day Bleeding.

BACKGROUND: Low anti-factor Xa level, indicative of inadequate enoxaparin dosing, has a significant association with 90-day venous thromboembolism events. The authors examined the pharmacodynamics of enoxaparin 40 mg twice daily and its correlation with anti-factor Xa level, postoperative venous thromboembolism, and bleeding. METHODS: Adult patients were admitted after plastic and reconstructive surgery and received enoxaparin 40 mg twice daily. Peak anti-factor Xa levels, which quantify enoxaparin's antithrombotic effect, were drawn, with a goal level of 0.2 to 0.4 IU/ml. Ninety-day symptomatic venous thromboembolism and clinically relevant bleeding were identified. RESULTS: The authors enrolled 118 patients who received enoxaparin 40 mg twice daily. Of these patients, 9.6 percent had low peak anti-factor Xa levels (<0.2 IU/ml), 62.6 percent had in-range peak anti-factor Xa levels (0.2 to 0.4 IU/ml), and 27.8 percent had high anti-factor Xa levels (>0.4 IU/ml). With enoxaparin 40 mg twice daily, 90.4 percent of patients received at least adequate prophylaxis. Patient weight predicted the rapidity of enoxaparin metabolism. Zero acute 90-day venous thromboembolism occurred. Eight patients (6.8 percent) had clinically relevant 90-day bleeding: clinical consequences ranged from cessation of enoxaparin prophylaxis to transfusion to operative hematoma evacuation. CONCLUSIONS: When enoxaparin 40 mg twice daily is provided, 90 percent of patients receive at least adequate venous thromboembolism prophylaxis (anti-factor Xa level >0.2 IU/ml). However, 27 percent of the overall population is overtreated (anti-factor Xa level >0.4 IU/ml). These pharmacodynamics data likely explain the low rate of 90-day acute venous thromboembolism (0 percent) and the high rate of clinically relevant bleeding (6.8 percent) observed. Future studies are needed to better optimize the risks and benefits of enoxaparin prophylaxis in plastic and reconstructive surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Bioequivalence of a biosimilar enoxaparin sodium to Clexane® after single 100 mg subcutaneous dose: results of a randomized, double-blind, crossover study in healthy volunteers.

PURPOSE: To demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence of a biosimilar enoxaparin to the reference drug, and to assess its safety and tolerability in healthy volunteers. PATIENTS AND METHODS: A randomized, double-blind, crossover, 2-sequence, single-dose study was conducted in healthy volunteers of both sexes. Participants were sequentially and randomly administered single subcutaneous injections of enoxaparin 100 mg manufactured by Rovi (test; Madrid, Spain) and Clexane® (enoxaparin 100 mg manufactured by Sanofi, reference) separated by a 1-week washout period. The primary PK/PD variables were maximum activity (Amax) and area under the effect curve from time 0 to the last measured activity (T) (AUEC0-T) and AUEC from time 0 to infinity (AUEC0-inf) of anti-FXa activity, and Amax and AUEC0-T of anti-FIIa activity. Secondary variables were Amax and AUEC0-T, AUEC0-inf of tissue factor pathway inhibitor, and the ratio of AUEC0-T anti-FXa to anti-FIIa activity. Biosimilarity would be shown when the 95% CI of the ratio of geometric least squares means (95% CI RGLSMs) of primary PK/PD parameters fell within the standard range of bioequivalence, ie, 80%-125%. RESULTS: The study sample consisted of 46 volunteers (33 males) aged 18-44 years and with body mass index ranging from 19.0 to 31.1 kg/m2. Three subjects did not complete the study. The curves of anti-FXa, anti-FIIa and tissue factor pathway inhibitor activities corresponding to administration of the test and reference products were comparable. The 95% CI RGLSMs of Amax, AUEC0-T and AUEC0-inf for anti-FXa activity were 94.6%-105.9%, 99.8%-108.0% and 100.0%-108.6% respectively; Amax and AUEC0-T for anti-FIIa activity were 94.7%-112.6% and 90.9%-117.9% respectively. In addition, the 95% CI RGLSMs of all secondary variables fell within the range 80%-125%. The incidence and types of adverse events after administration of the test and reference drugs were similar. CONCLUSION: The results conclusively showed that the enoxaparin manufactured by Rovi is equivalent to the reference enoxaparin in all primary and secondary PK/PD parameters, as required by the European Medicines Agency to grant marketing authorization to a biosimilar low molecular-weight heparin.

Population pharmacokinetics of enoxaparin in early stage of paediatric liver transplantation.

AIMS: Preventing post-liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT. METHODS: Anti-Xa activity time-courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R. RESULTS: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi  = CLTYP * (BWPREOP /70)3/4 ; Vi  = VTYP * (BW(t)/70)1 ; where typical clearance (CLTYP ) and typical volume of distribution (VTYP ) were 1.23 l h-1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg-1  12 h-1 were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg-1  12 h-1 are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 from the first day. CONCLUSION: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

BACKGROUND: There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. OBJECTIVE: To characterize the pharmacokinetics of enoxaparin in pediatric patients. METHODS: A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. RESULTS: A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m2). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. CONCLUSIONS: Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m2 are required.

Enoxaparin Population Pharmacokinetics in the First Year of Life.

AIMS: Enoxaparin dosing requirements in the first year of life can be highly variable. Characterization of pharmacokinetics in this patient population can assist in dosing. METHODS: Patients less than 1 year postnatal age who received enoxaparin and had an anti-factor Xa activity level drawn as inpatients were identified through the pharmacy database over a 5-year period. Patients on renal replacement therapy or with hyperbilirubinemia were excluded. Data collection included demographic variables, indication for enoxaparin, enoxaparin doses, anti-factor Xa activity levels, serum creatinine, hemoglobin, hematocrit, platelet count, and urine output over the previous 24 hours. Population pharmacokinetic analysis was performed with NONMEM. RESULTS: A total of 182 patients [male 50%, median 100 days postnatal age (range: 4-353 days)] met the study criteria. Patients received median 22 doses (range: 1-526) at a mean starting dose of 1.38 ± 0.43 mg/kg with median 5 (range: 1-56) anti-factor Xa activity levels measured. A 1-compartment proportional and additive error model best fits the data. Allometrically scaled weight significantly decreased the objective function value, as did serum creatinine on clearance, and postmenstrual age (PMA) on volume of distribution. When evaluated graphically, dosing based on PMA appeared to have less variability as compared to postnatal age-based dosing. CONCLUSIONS: Dosing of enoxaparin in infants younger than 1 year should incorporate PMA.

The use of anti-factor Xa monitoring in a selection of patients receiving enoxaparin at a large academic medical center.

Therapeutic enoxaparin is commonly used over heparin because of its favorable pharmacokinetic profile and ease of administration. Monitoring of the anticoagulant response, if necessary, is done with anti-factor Xa levels. Currently, it is suggested that monitoring may be beneficial in patients who are overweight and those with renal dysfunction. This study aimed to characterize the use of enoxaparin at a large-academic medical center in patients >150 kg, <45 kg and in those with renal dysfunction, and to describe the rate of anti-factor Xa monitoring in these patients. There were 273 patients included in the study: n = 96 for <45 kg arm, n = 111 for >150 kg arm and n = 66 for renal dysfunction arm. Less than 30 % of patients in each arm had low molecular weight heparin anti-factor Xa levels drawn. Of these only half were drawn as peak levels (4 h post dose). Overall rates of anti-factor Xa monitoring was low. It was found that obese patients achieved therapeutic anticoagulation with lower than recommended doses; underweight patients were often subtherapeutic on the recommended doses; and patients with renal dysfunction tended to have therapeutic to subtherapeutic anti-factor Xa levels. Ultimately, this evaluation showed that enoxaparin has unpredictable pharmacokinetics in these three high-risk patient populations and anti-factor Xa monitoring may be necessary to ensure therapeutic levels and appropriate dosing.