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

Abstract

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01244-4.

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.…”

Guillain-Barré syndrome associated with COVID-19 infection – Case Report and literature review

“…Berrra et al hypothesized that the pathogenesis of GBS after COVID-19 may be also indirectly related to ICU treatment, thrombotic complications in coagulopathy, endotheliopathy, and/or vasculitis involving vasa nervorum [15]. Inadequate dosing of thromboprophylaxis in the population of critically ill COVID-19 patients may be one of the factors predisposing to neuropathies [16]. In addition, some patients have been diagnosed with autoimmune neurological disorders due to COVID-19, including Guillain-Barré Syndrome (GBS) [12].…”

The impact of bacterial superinfections on the outcome of critically ill patients with COVID-19 associated acute respiratory distress syndrome (ARDS) – a single-centre, observational cohort study

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“…It analyses patient data previously gathered by Piwowarczyk et al . [ 11 ] for their study concerning the pharmacokinetics of nadroparin in critically ill patients with COVID-19. The main aims of that study were to assess concentrations of nadroparin and determine the possibility of achieving a target appointment of this low-molecular-weight heparin using a single or double injection regime.…”