Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels

Abstract

IntroductionThe optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and < 2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics. Methods Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥ 0.4 IU/mL (efficacy) and < 2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics. Results Patients (n = 137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (± 16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥ 80 kg) had a low probability (< 29%) of anti-Xa levels ≥ 0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (< 50 kg), had a high probability (> 70%) of peak anti-Xa levels < 2.0 IU/mL. Conclusion Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL.

Is the current therapeutic dosage of nadroparin adequate for neonates and infants under 8 months with thromboembolic disease? a population pharmacokinetic study from a national children’s medical center

“…A population PK model was developed to characterize the relationship between dose and anti-Xa levels in neonates and infants receiving thromboprophylactic treatment with nadroparin at a dose of 150–200 IU/kg q12 h. To our knowledge, only a few previous population PK models of nadroparin have been published, including studies in morbidly obese bariatric surgery patients ( Diepstraten et al, 2015 ), pediatric open heart surgery patients ( Laporte et al, 1999 ), patients receiving hemodialysis ( Jaspers et al, 2022 ), critically ill adult patients ( Diepstraten et al, 2023 ), and COVID-19 intensive care unit patients ( Piwowarczyk et al, 2023 ; Romano et al, 2023 ). However, no population PK analyses have been conducted for nadroparin in neonates and infants.…”

Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phospho-diesterase-1 (NPP1) – a promising target for the immunotherapy of cancer

“…Dalteparin (3), dosed once daily with 120 IU/kg s.c., or i.v., respectively, reaches 0.6-2.2 IU/ml ( 49 ). Nadroparin (4) applied s.c. in doses of 41 U/kg, or 166 U/kg, respectively, results in maximal concentrations of 0.61-1.34 IU/ml ( 50 ). Enoxaparin (5), applied s.c., or initially by i.v.…”