NM is utilized for several indications. First, it is employed to improve the acute symptoms associated with pancreatitis, including acute pancreatitis, acute exacerbation of chronic pancreatitis, postoperative acute pancreatitis, acute pancreatitis after pancreatic angiography, and traumatic pancreatitis. Second, NM is used in the management of disseminated intravascular coagulopathy. Last, it serves as a preventive measure against blood coagulation during extracorporeal circulation in patients with bleeding lesions or tendencies, commonly observed during procedures such as hemodialysis, plasmapheresis, and ECMO. In recent times, NM has emerged as a potential treatment for pneumonia linked to COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [18–21].
Our previous study demonstrated the effective and safe use of NM as a regional anticoagulant in patients undergoing VA ECMO [16]. We administered either NM or unfractionated heparin (UFH) and specifically compared the aPTT of blood samples obtained from the patient's central vein with blood samples drawn from the ECMO circuit. The results revealed no statistically significant difference between the median aPTT of the patient sample (72.84 seconds) and the median aPTT of the ECMO sample (72.95 seconds) when UFH was administered. However, upon switching to NM, a significant difference was observed. The median aPTT of the ECMO sample increased to 73.13 seconds, while the median aPTT of the patient sample decreased to 68.42 seconds, with a p-value of 0.031. Moreover, when addressing bleeding adverse events, we switched from UFH to NM, resulting in significant improvement in bleeding symptoms for four patients with cannulation site bleeding, one patient with gingival bleeding, and one patient with hematochezia. Based on our previous study, we recognized the necessity for a quantitative analysis of the PK and PD of NM to enhance our understanding of its administration in ECMO patients.
To the best of our knowledge, there are no existing clinical studies that have developed population PK/PD models for NM in patients. We developed and compared two PK/PD models, one utilizing central venous samples from patients and the other utilizing samples from the ECMO circuit. Samples obtained from the ECMO circuit exhibited higher concentrations compared to samples collected from the patient's central vein, providing a potential explanation for the observed higher aPTT levels in ECMO samples compared to patient samples in both this study and previous studies [14, 16]. The PK profiles of NM in both sample types were well described by two-compartment models. In our study, the patient model exhibited a distribution half-life (t1/2α) of 0.54 minutes and an elimination half-life (t1/2β) of 19.7 minutes. On the other hand, the ECMO model demonstrated a t1/2α of 1.2 minutes and a t1/2β of 51.4 minutes. These results were comparable to those of other studies in Asian populations [22]. In a Phase 1 study conducted in Japan, the observed t1/2α and t1/2β were 1.1 minutes and 23.1 minutes, respectively. A study involving healthy adults in China reported t1/2α ranging from 3.65 to 3.78 minutes and t1/2β ranging from 112.42 to 129.19 minutes [23]. However, a study conducted with dialysis patients revealed a half-life of 8 minutes for NM [24]. This study provided evidence supporting the suitability of NM as an anticoagulant in patients with a heightened vulnerability to bleeding during ECMO or CRRT, owing to its remarkably short half-life compared to UFH (60–90 minutes), argatroban (45 minutes), and bivalirudin (25 minutes) [13, 17, 25–27]. According to our two-compartment model, following completion of dosing, the concentration declines rapidly due to the extremely short t1/2α. As a result, even if t1/2β is prolonged, the concentration becomes very low during the elimination phase. However, the steady-state concentration achieved through continuous infusion may significantly differ from the steady-state concentration determined solely by a single half-life of 8 minutes, depending on the interplay between t1/2α and t1/2β.
Among various PD models, the final turnover model provided a robust explanation for the relationship between NM concentration and the corresponding change in aPTT. This model effectively captures how NM inhibits the mechanism responsible for the decrease in aPTT. A turnover model is a mechanistic approach used to describe drug-induced indirect responses by elucidating the dynamic equilibrium between response production and response loss, providing insights into the underlying mechanisms altered by the drug [28, 29]. In our final PD model, we demonstrated the increase in aPTT by an increase in NM as a mechanism by which NM inhibits the loss of response, i.e., inhibits the decrease in aPTT. To date, there have been no studies that have modeled the relationship between NM exposure and aPTT level. However, the IC50s of our models were comparable to those of Hitomi et al. [30]. In their study, NM, with a molecular weight of 347.37 g/mol, exhibited an IC50 value of 3.0 x 10− 9 M (1.0421 µg/L) for plasma kallikrein inhibition and an IC50 value of 3.3 x 10− 7 M (114.63 µg/L) for inhibiting human Hagmann factor fragment. Additionally, the concentration of NM required to double the aPTT was 5.0 x 10− 7 M (173.69 µg/L).
When Monte Carlo simulations were performed using the final model, the PK profiles of the patient and ECMO models were significantly different, while the PD profiles were not significantly different. In a study conducted in 1972 involving adult patients not on ECMO, maintaining an aPTT within the range of 1.5 to 2.5 times the normal value was associated with a reduced occurrence of recurrent venous thromboembolic events [31]. The current clinical recommendations suggest maintaining an aPTT level of 40 to 80 seconds during ECMO, which corresponds to 1.5 to 2.5 times the pretherapy baseline level [17, 32–35]. However, this recommendation has not been validated in randomized controlled trials or specifically in patients undergoing ECMO therapy [3]. To attain the target aPTT level, Park et al. administered NM at a dose range of 0.14–0.98 mg/kg/h (equivalent to 9.8–68.6 mg/h for a 70 kg weight) [26], while Lee et al. administered NM at a median dose of 17.7 mg/h (range: 9.8–21.7 mg/h) [16]. A systematic review of studies involving the use of NM as an anticoagulant in ECMO patients revealed that the mean dose ranged from 0.46 to 0.67 mg/kg/h (equivalent to 32.2–46.9 mg/h for a 70 kg patient) [17]. Based on the findings from these studies, we conducted PK/PD simulations using 10 mg increments of NM infusion rates ranging from 10 mg to 50 mg. At an NM infusion rate of 50 mg/h, the steady-state concentration of NM in the patient samples was generally below 150 µg/L, whereas that in the ECMO machine samples was approximately 875 µg/L. However, there was no significant difference in aPTT level between the patient samples (40 seconds) and the ECMO samples (45 seconds). These results are consistent with the actual observed data in this study, where despite higher concentrations of NM measured in the ECMO samples compared to the patient samples, there was not a significant difference in aPTT level. This finding was accurately reflected in the PK/PD model. The significant interindividual variation observed in the difference between the aPTT levels of ECMO samples and patient samples within each patient highlights the potential benefits of personalized treatment guided by robust models in maintaining optimal aPTT levels.
ECMO has been used worldwide, and its frequency of use is increasing due to the COVID-19 pandemic. Despite technological improvement and accumulated clinical experiences, the optimal anticoagulation strategies and monitoring are not well established, and major bleeding remains both the leading cause of mortality in patients with ECMO and the Achilles heel of ECMO. In this study, we proved the efficacy of NM as a regional anticoagulant comparing the PK/PD profiles of NM in both patient and ECMO samples. Also, the changes in aPTT level induced by NM were represented by a turnover model, in which NM inhibited the decrease in aPTT. However, in real clinical practice, there is a lack of research on the actual correlation between concentration and adverse events of NM use. Considering diverse clinical situations and variables, additional research is needed to optimally adjust and titrate the dose of NM in real practice.
This study has some limitations. First, the study had a limited number of patients, which hindered the identification of significant covariates, and the sampling number for each patient was insufficient for the development of a robust PD model with good predictive performance. Consequently, large between-subject variability and imprecise parameter estimates were observed, highlighting the need for caution when extrapolating the findings of this model. Second, as shown in the individual fit plots, the model exhibited suboptimal fitting for a small subset of patients. It appeared that a few patients were documented as continuing their medication despite its discontinuation; due to the absence of any justifiable grounds for exclusion or modification of this data, they were retained for the purpose of model development. Third, we were unable to evaluate other PD markers such as activated clotting time (ACT), prothrombin time (PT), anti-factor Xa, and antithrombin activity, in addition to aPTT. Although ACT and PT data were collected, they had significant missing data and could not be used in model development. However, aPTT represents the most frequently recommended test in clinical guidelines and consensus statements.