Population pharmacokinetics of nadroparin for thromboprophylaxis in COVID‐19 ICU patients

AIM: Nadroparin is administered to COVID-19 ICU patients as thromboprophylaxis. Despite existing population pharmacokinetic (PK) models for nadroparin in literature, the population PK of nadroparin in COVID-19 ICU patients is unknown. Moreover, optimal dosing regimens achieving anti-Xa target levels (0.3-0.7 IU/mL) are unknown. Therefore, a population PK analysis was conducted to investigate different dosing regimens of nadroparin in COVID-19 ICU patients. METHODS: Anti-Xa levels (n=280) from COVID-19 ICU patients (n=65) receiving twice daily (BID) 5700IU of subcutaneous (sc) nadroparin were collected to perform a population PK analysis with NONMEM v7.4.1. Using Monte Carlo simulations (n=1000), predefined dosing regimens were evaluated. RESULTS: A one-compartment model with an absorption compartment adequately described the measured anti-Xa levels with inter-individual variability (IIV) estimated for clearance (CL). Inflammation parameters CRP, D-dimer, and CKD-EPI-eGFR allowed to explain the IIV of CL. Moreover, CL was decreased in patients receiving corticosteroids (22.5%) and vasopressors (25.1%). Monte Carlo simulations demonstrated that 5700IU BID was the most optimal dosing regimen of the simulated regimens for achieving prespecified steady-state t=4h anti-Xa levels with 56.7% on target (0.3-0.7 IU/mL). CONCLUSIONS: In our study, clearance of nadroparin is associated with an increase in inflammation parameters, use of corticosteroids, vasopression, and renal clearance in critically ill patients. Furthermore, of the simulated regimens, targeted anti-Xa levels were most adequately achieved with a dosing regimen of 5700IU BID. Future studies are needed to elucidate the underlying mechanisms of found covariate relationships.