L.G.R. Romano (1), N.G.M. Hunfeld (2,3), M.J.H.A. Kruip (1), H. Endeman (3), T. Preijers (2)
(1) Department of Hematology, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; (2) Department of Hospital Pharmacy, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; (3) Department of Intensive Care, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
Introduction:
COVID-19 ICU patients receive thromboprophylaxis with low molecular weight heparin (LMWH).[1] However, optimal dose regimens achieving target anti-Xa levels (0.3-0.7 IU/mL) are unknown. Moreover, target levels need to be measured on t=4h after dose administration, which can be challenging in clinical practice. Currently, a population pharmacokinetic (popPK) model describing anti-Xa levels after nadroparin administration for morbidly obese bariatric non-COVID-19 surgery patients exists in literature.[2] As COVID-19 related coagulopathy is associated with high levels of procoagulant factors, it is expected that COVID-19 ICU patients have different individual PK parameters. As these individual PK parameters allow to evaluate whether limited sampling strategies (LSSs) other than t=4h after dose are adequate as well, it is important that a well-performing popPK model is applied to estimate them. Moreover, using individual PK parameters the most optimal dose regimen for anti-Xa target level achievement can be investigated as well.
Objectives
- Assessing the popPK parameters describing anti-Xa levels in COVID-19 ICU patients receiving thromboprophylaxis with nadroparin 5700IU twice daily
- Assessing the most optimal prophylactic dosing scheme
- Establishing multiple LSSs
Methods:
During the first COVID-19 pandemic wave in The Netherlands, anti-Xa levels from 65 COVID-19 ICU patients were collected and applied to evaluate the previously published popPK model. As the second pandemic wave allowed to obtain more data, these were randomly allocated to the modeling as well as a validation cohort. Population PK analysis was performed using NONMEM v7.4.1.[3] As to evaluate the bias (<15%) and imprecision (<25%) from the LSSs using the relative mean prediction error (rMPE) and relative root mean squared error (rRMSE), respectively, Monte Carlo simulations allowed to construct anti-Xa level versus time curves (n=2,000) using the final model. Moreover, individual PK parameters for the modeling cohort were obtained by maximum a posteriori Bayesian estimation and were used to investigate the most adequate dosing regimen.
Results:
On the basis of goodness-of-fit plots, the previously published model demonstrated inadequate performance. A one-compartment disposition model with an absorption compartment was constructed, which adequately described the measured anti-Xa levels with an estimated (RSE%) absorption rate of 0.28 h-1 (28%), volume of distribution of 11.0 L (22%) and a clearance (CL) of 2230 mL h-1 (12%). For the final model, IIV from CL was 34.9% (21%). With rising values for C-reactive protein, D-dimer, or estimated glomerular filtration rate (eGFR, CKD-EPI), CL was increased. Use of corticosteroids or vasopressors decreased CL with 22.5% and 25.1%, respectively. The final model was able to describe the anti-Xa levels from the validation cohort adequately. Monte Carlo simulations demonstrated that a LSS having two samples (t=4h and after a consecutive dose t=2h-8h) provided accurate estimates for individual CL (range rMPE: 1.29% – 1.91%, rRMSE: 19.4% – 24.8%) and anti-Xa levels (range rMPE: 1.01% – 2.87%, rRMSE: 16.2% – 22.2%). Furthermore, twice daily dosing of 5700IU nadroparin was the most adequate dosing regimen for achieving targeted anti-Xa levels (0.3 – 0.7 IU/mL).
Conclusions:
In COVID-19 ICU patients, individual PK parameters describing anti-Xa levels obtained after nadroparin administration are clearly influenced by inflammation. Furthermore, LSSs were established with less stringent sample timing than the current t=4h, which may facilitate clinical practice. As a starting dose, targeted anti-Xa levels were most adequately achieved using nadroparin 5700IU twice daily.
References:
[1] Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, et al. Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19. J Thromb Haemost. 2020.
[2] Diepstraten J, Janssen EJ, Hackeng CM, van Dongen EP, Wiezer RJ, van Ramshorst B, et al. Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint. Eur J Clin Pharmacol. 2015;71(1):25-34. [3] Bauer RJ. NONMEM Tutorial Part I: Description of Commands and Options, with Simple Examples of Population Analysis. CPT Pharmacometrics Syst Pharmacol. 2019;8(8):525-37.
Reference: PAGE 30 (2022) Abstr 9990 [www.page-meeting.org/?abstract=9990]
Poster: Clinical Applications