Population Pharmacokinetics of Enoxaparin in Pediatric Patients

Moffett, Brady S.; Lee-Kim, YoungNa; Galati, Marianne; Mahoney, Donald H.; Shah, Mona D.; Teruya, Jun; Yee, Donald L.

doi:10.1177/1060028017734234

Cited by 12 publications

(15 citation statements)

References 26 publications

(41 reference statements)

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“… 6 , 7 Two population PK models of enoxaparin in children have been published which use allometrically scaled Wt as a covariate on clearance. 5 , 17 However, when both models were fitted to our dataset and evaluated using pcVPCs overlaid with the data, they performed well overall but significantly underpredicted concentration in the overweight/obese group (see Figure 3 ). This is probably due to CL being overestimated as a result of the assumption of proportionality to Wt.…”

Section: Discussionmentioning

confidence: 91%

“… 3 , 4 A recent population analysis showed that this dose has a 72.3% probability of achieving the aXa concentration target in hospitalised paediatric patients. 5 Maintenance dosing based on total body weight (Wt) implies that enoxaparin clearance is linearly proportional to Wt. However, this has often been found to be inaccurate in overweight/obese individuals.…”

Section: Introductionmentioning

confidence: 99%

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Optimal dosing of enoxaparin in overweight and obese children

Derbalah

Duffull

Sherwin

et al. 2022

Brit J Clinical Pharma

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Aim Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen. Methods Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti‐Xa) assay. Patients provided a total of 552 anti‐Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction‐corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed‐effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children. Results Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one‐compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat‐free mass with an estimated exponent of 0.712 (CI 0.66‐0.76) was the most influential covariate on clearance while linear fat‐free mass was selected as the covariate on volume. Simulations from the model showed that fat‐free mass‐based dosing could achieve the target anti‐Xa activity at steady state in 77.5% and 78.2% of obese and normal‐weight children, respectively, compared to 65.2% and 75.5% for standard total body weight‐based dosing. Conclusions A population PK model that describes the time course of anti‐Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Optimal dosing of enoxaparin in overweight and obese children

Derbalah

Duffull

Sherwin

et al. 2022

Brit J Clinical Pharma

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“…Based on adult data on enoxaparin with a creatinine clearance (CrCL) of <30 mL/min should have an empiric dose adjustment to 1 mg/kg daily. 3 In a pharmacokinetic study of enoxaparin in pediatric patients published by Moffett et al, 4 a 30% reduction in starting dose was recommended in patients with a CrCL of <30 mL/min. Given the limited available information, and by taking a more conservative approach, the dose was reduced to 1 mg/kg daily, which was a 50% reduction.…”

Section: Discussionmentioning

confidence: 99%

A Distinctive Approach to Venous Thromboembolism Treatment in a Pediatric, Hemodialysis Patient: A Case Report

Koury¹,

Schnakenberg²,

Villasenor³

et al. 2021

The Journal of Pediatric Pharmacology and Therapeutics

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Enoxaparin is a low molecular weight heparin (LMWH) that is the mainstay for treatment of pediatric patients with a venous thromboembolism, which provides better compliance compared with the use of unfractionated heparin (UFH) in long-term anticoagulation. Although data are limited in pediatric patients with renal insufficiency, enoxaparin can be used in this population. Data related to its use in hemodialysis (HD) pediatric patients is almost non-existent. A major concern for enoxaparin use in patients with renal insufficiency or for those on HD is bleeding. A few studies in adults showed an increased risk of bleeding, but the risk was similar to that of UFH when the two were compared. This case report describes the use of enoxaparin in an 8-year-old female who is on hemodialysis, without any bleeding or clotting complications. Although systematic trials are needed to support the safety and efficacy of LMWH in pediatric patients with renal dysfunction or on HD, this case will provide limited information for enoxaparin use in this population.

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“…LMWH, mainly enoxaparin, is the primary choice for pediatric patients because of its stable pharmacokinetics and greater bioavailability [ 102 ]. A pharmacokinetic study of enoxaparin in children and adolescents proposed an initial dose of 1.0 mg/kg subcutaneously and every 12 h thereafter [ 103 ]. Although the recommendation for LMWH drug monitoring is the target anti-Xa activity [ 101 , 104 ], a recent retrospective cohort study showed that the proposed guidelines did not consistently lead to therapeutic anti-Xa levels [ 105 ].…”

Section: Management Of Pediatric Apsmentioning

confidence: 99%

Managing Antiphospholipid Syndrome in Children and Adolescents: Current and Future Prospects

et al. 2021

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Pediatric antiphospholipid syndrome (APS) is a rare acquired multisystem autoimmune thromboinflammatory condition characterized by thrombotic and non-thrombotic clinical manifestations. APS in children and adolescents typically presents with large-vessel thrombosis, thrombotic microangiopathy, and, rarely, obstetric morbidity. Non-thrombotic clinical manifestations are frequently seen in pediatric APS and may be present even before the vascular thrombotic events occur. We review insights into the pathogenesis of APS and discuss potential targets for therapy. The identification of multiple immunologic abnormalities in patients with APS reveals molecular targets for current or future treatment. Management strategies, especially for APS in adolescents, require screening for additional prothrombotic risk factors and consideration of counseling regarding contraceptive strategies, lifestyle recommendations, treatment adherence, and mental health issues associated with this autoimmune thrombophilia. The main goal of therapy in pediatric APS is the prevention of thrombosis. The management of acute thrombosis events in children and adolescents is the same as for primary APS, which involves isolated occurrences, and secondary APS, which is seen in association with another autoimmune disease, e.g., systemic lupus erythematosus. A pediatric hematologist should be consulted so other differential thrombophilic conditions can be eliminated. Therapy includes unfractionated heparin or low-molecular-weight heparin followed by vitamin K antagonists. Treatment of catastrophic APS involves triple therapy (anticoagulation, intravenous corticosteroid pulse therapy, and plasma exchange) and may include intravenous immunoglobulin for children and adolescents with this condition. New drugs such as eculizumab and sirolimus seem to be promising drugs for APS.

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Population Pharmacokinetics of Enoxaparin in Pediatric Patients

Abstract: 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 m are required.

Cited by 12 publications

References 26 publications

Optimal dosing of enoxaparin in overweight and obese children

Optimal dosing of enoxaparin in overweight and obese children

A Distinctive Approach to Venous Thromboembolism Treatment in a Pediatric, Hemodialysis Patient: A Case Report

Managing Antiphospholipid Syndrome in Children and Adolescents: Current and Future Prospects

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