Abstract Number: LPB0059
Meeting: ISTH 2021 Congress
Theme: COVID and Coagulation » COVID and Coagulation, Clinical
Background: An increased incidence of thrombo-embolic events has been described in Coronavirus Disease 2019 (COVID-19) patients, especially in critically-ill patients. In response, ISTH guidelines consider use of intermediate-dose low-molecular-weight heparins (LMWH) in critically-ill COVID-19 patients. Therefore, twice daily nadroparin dosing can been applied to prevent thrombo-embolic events. Although population pharmacokinetic (PK) parameters of nadroparin are unknown in ICU COVID-19 patients, these parameters would allow evaluation of the proposed dosing schemes from current guidelines.
Aims: To construct a population PK model describing anti-Xa levels subsequent to nadroparin administration, allowing assessment of population PK parameters and their associated interpatient variability (IIV) in COVID-19 Intensive Care Unit (ICU)-patients.
Methods: Retrospective data of 65 ICU patients with at least one positive SARS-CoV-2 RT-PCR test were included (Table 1/Results). At start of ICU admission, patients received twice daily 5700 IU nadroparin according to local protocol. Anti-Xa sampling was applied routinely daily. Population PK parameters were estimated using nonlinear mixed-effect modelling (NONMEM v7.4.1). Data collection was approved by the local ethics committee.
Results: Anti-Xa level versus time profiles were adequately described using a population PK model with one elimination and one absorption compartment (Figure 2). Including a transit-compartment did not result in significantly better data description. Population PK parameter estimates and IIV (%) were: absorption rate: 0.245 h-1, clearance (CL): 2010 mL/h (33.9%), V1: 10.0 L. CL increased exponentially with rising CRP, D-dimer and renal function (CKD-EPI eGFR). When applying corticosteroids or vasopressors, CL was decreased by 22.4% and 20.3% respectively.
| Total population No. (%) or median [interquartile range] |
Male No. (%) or median [interquartile range] |
Female No. (%) or median [interquartile range] |
|
| Total no. of patients | 65 | 40 | 25 |
| Age (years) | 62 [53 – 68.5] | 66 [53 – 71] | 60.5 [54.2 – 65] |
| Body weight (kg) | 89 [78 – 100] | 90.5 [83.1 – 105] | 85 [72 – 95] |
| CKD-EPI eGFR (ml/min) | 84.3 [51.8 – 99.6] | 92.8 [52.6 – 101] | 66.9 [34.9 – 93.8] |
| Leukocytes (109/l) | 9.5 [7.2 – 12.6] | 10.1 [7.47 – 13.6] | 9.3 [5.6 – 11.5] |
| D-dimer (mg/l) | 1.32 [0.74 – 2.24] | 1.27 [0.73 – 2.28] | 1.32 [1.02 – 2.22] |
| CRP (mg/l) | 119 [74.7 – 195] | 126 [74.7 – 205] | 114 [78.7 – 165] |
| Vasopression use at start | 57 (88) | 35 (88) | 22 (88) |
| Corticosteroid use during ICU admission | 42 (65) | 26 (65) | 16 (64) |
General characteristics of the study population
Prediction-corrected Visual Predictive Check of the final model. Black dots represent the measured anti-Xa levels. Solid grey line represents the median and the dashed grey lines represent the 2.5th and 97.5th quantiles of the measured anti-Xa levels. Red and blue-shaded areas show the 95% confidence intervals for the predicted individual anti-Xa levels, as obtained by 2000 Monte Carlo simulations using the final model.
Conclusions: In critically-ill COVID-19 patients, measured anti-Xa levels were adequately described by the established population PK model. Our model shows that nadroparin clearance, reported as anti-Xa levels, is influenced by inflammation. This model will be used to evaluate limited sampling schemes for anti-Xa to facilitate blood sampling in clinical practice.
To cite this abstract in AMA style:
Romano LGR, Endeman H, Hunfeld NGM, Preijers T. Population Pharmacokinetics of Anti-Xa Levels in COVID-19 ICU Patients Receiving Prophylaxis for Thrombo-embolic Events Using Nadroparin [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/population-pharmacokinetics-of-anti-xa-levels-in-covid-19-icu-patients-receiving-prophylaxis-for-thrombo-embolic-events-using-nadroparin/. Accessed September 24, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/population-pharmacokinetics-of-anti-xa-levels-in-covid-19-icu-patients-receiving-prophylaxis-for-thrombo-embolic-events-using-nadroparin/