Low and Highly Variable Exposure to Prophylactic LMWH Nadroparin in Critically Ill Patients: Back to the Drawing Board for Prophylactic Dosing?

Abstract

Background and Objective Low-molecular-weight heparins are routinely administered to patients in the intensive care unit to prevent venous thromboembolisms. There is considerable evidence that low-molecular-weight heparin doses should be personalised based on anti-Xa levels, but pharmacokinetic data in intensive care unit patients are lacking. This study aimed to characterise the pharmacokinetics and associated variability of the low-molecular-weight heparin nadroparin in critically ill patients. Methods Critically ill adult patients who were admitted to the intensive care unit and received nadroparin for prophylaxis of venous thromboembolism were included in a study. Population pharmacokinetic analysis was performed by means of parametric non-linear mixed-effects modelling (NONMEM). Results A total of 30 patients were enrolled with 12 patients undergoing continuous veno-venous hemodialysis and 18 patients not undergoing continuous veno-venous hemodialysis. Very high variability in pharmacokinetics was observed with an inter-individual variability in the volume of distribution of 63.7% (95% confidence interval 46.5-90.6), clearance of 166% (95% confidence interval 84.7-280) and relative bioavailability of 40.2% (95% confidence interval 29.5-52.6). We found that standard doses of 2850 IE and 5700 IE of nadroparin resulted in sub-prophylactic exposure in critically ill patients. Conclusions Low exposure and highly variable pharmacokinetics of nadroparin were observed in intensive care unit patients treated with a prophylactic dose. It can be debated whether nadroparin is currently dosed optimally in intensive care unit patients and our findings encourage the investigation of higher and tailored dosing of nadroparin in the critically ill.

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.…”