Dabigatran Plasma Concentrations Research Articles

Dabigatran pharmacokinetic-pharmacodynamic in sheep: Informing dose for anticoagulation during cardiopulmonary bypass.

The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. Five sheep were given intravenous dabigatran 4mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480min, and 24h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15mg/kg administered 120min after dabigatran 4mg/kg and its effect on R-time was observed. A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453L/min/70kg), intercompartment clearance (Q 0.268L/min/70kg), central volume of distribution (V1 2.94L/70kg), peripheral volume of distribution (V2 9.51L/70kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2mg/L) eliciting half of the maximal effect (EMAX 180min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04min. Idarucizumab 15mg/kg reduced R-time by approximately 5min. Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25mg/kg followed by a maintenance infusion of dabigatran 0.0175mg/kg/min for 30min and a subsequent infusion dabigatran 0.0075mg/kg/min achieves a steady state target concentration of 5mg/L in a sheep model.

DOAC plasma concentration upon hospital admission in a cohort of trauma patients. An observational real-life study.

Due to a better safety profile, direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. However, little is known about DOAC plasma concentrations in trauma patients upon hospital admission. Thus, we investigated the frequency and extent of DOAC possible over- and underdosing in trauma patients upon hospital admission. In this single-center retrospective study, DOAC plasma concentrations of adult trauma patients were analyzed with specific calibrated anti-IIa (dabigatran) and anti-Xa (apixaban, edoxaban and rivaroxaban) tests within 4h after hospital admission. A total of 210 trauma patients, admitted between 2019 and 2022, were included in the analyses. Low DOAC levels < 30ng/mL were detected in 13.3% of the patients. In 7.1% of the patients, DOAC plasma levels ranged between 300-399ng/mL and further 7.1% exhibited plasma concentrations > 400ng/mL. The highest incidence of high to very high DOAC plasma concentration was observed for patients on rivaroxaban and dabigatran. A moderate correlation was observed between dabigatran plasma concentration and estimated glomerular filtration rate (rho = - 0.5338, p = 0.0003). For rivaroxaban no clear association between plasma concentration and liver or renal function could be detected. Patients on statins had significantly higher DOAC concentration in comparison with those not taking statins (153 (76-274) vs 108 (51-217) ng/mL, p = 0.046). The current study revealed that patients on dabigatran and rivaroxaban were prone to higher DOAC plasma levels upon hospital admission in comparison with apixaban and edoxaban. DOAC plasma level measurement in trauma patients might be warranted due to unpredictively low or high plasma concentrations. However, the clinical impact of altered plasma levels on both, bleeding and thromboembolic events, remains to be determined by future studies.

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants.

To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate). PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n= 12) or dabigatran 75 mg (n= 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment. After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported. Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.

The Distribution of the Genotypes of ABCB1 and CES1 Polymorphisms in Kazakhstani Patients with Atrial Fibrillation Treated with DOAC.

Nowadays, direct oral anticoagulants (DOACs) are the first-line anticoagulant strategy in patients with non-valvular atrial fibrillation (NVAF). We aimed to identify the influence of polymorphisms of the genes encoding P-glycoprotein (ABCB1) and carboxylesterase 1 (CES1) on the variability of plasma concentrations of DOACs in Kazakhstani patients with NVAF. We analyzed polymorphisms rs4148738, rs1045642, rs2032582 and rs1128503 in ABCB1 and rs8192935, rs2244613 and rs71647871 CES1 genes and measured the plasma concentrations of dabigatran/apixaban and biochemical parameters in 150 Kazakhstani NVAF patients. Polymorphism rs8192935 in the CES1 gene (p = 0.04), BMI (p = 0.01) and APTT level (p = 0.01) were statistically significant independent factors of trough plasma concentration of dabigatran. In contrast, polymorphisms rs4148738, rs1045642, rs2032582 and rs1128503 in ABCB1 and rs8192935, rs2244613 and rs71647871 CES1 genes did not show significant influence on plasma concentrations of dabigatran/apixaban drugs (p > 0.05). Patients with GG genotype (138.8 ± 100.1 ng/mL) had higher peak plasma concentration of dabigatran than with AA genotype (100.9 ± 59.6 ng/mL) and AG genotype (98.7 ± 72.3 ng/mL) (Kruskal-Wallis test, p = 0.25). Thus, CES1 rs8192935 is significantly associated with plasma concentrations of dabigatran in Kazakhstani NVAF patients (p < 0.05). The level of the plasma concentration shows that biotransformation of the dabigatran processed faster in individual carriers of GG genotype rs8192935 in the CES1 gene than with AA genotype.

Dabigatran Dosing Proposal for Adults With Atrial Fibrillation: Stress-Testing Renal Function Range in Real World Patients.

Dabigatran is the first of four direct-acting oral anticoagulants approved to prevent stroke in adult patients with atrial fibrillation using a fixed two-dose scheme compared with warfarin dosing adjusted to a prothrombin time range associated with optimal risk reduction in stroke and serious bleeding. The pivotal phase III trial found dabigatran, depending on dose, is superior to warfarin in stroke reduction and similar in bleeding risk while also showing dabigatran efficacy and safety correlate with steady-state plasma concentrations. Because the relationship between dabigatran dose and plasma concentration is highly variable, a previously developed population pharmacokinetic model of over 9,000 clinical trial patients was used as a basis for simulations comparing the performance of dosing via the drug label to other proposed doses and regimens. Assessment of dosing regimen performance was based on simulations of trough plasma levels within the therapeutic concentration range of 75-150 ng/mL over a renal function range of 15-250 mL/min creatinine clearance, representing extremes for real-world patients. An improved regimen that best achieves this therapeutic range was identified, requiring five different dosing schedules, corresponding to specified renal function ranges, compared with the two approved in the label. The discussion focuses on how this information could better inform patient outcomes and future dabigatran development.

Adherence to protocols for the use of reversal agents in patients treated with direct oral anticoagulants

Objectives This study aimed to evaluate the adherence to protocols for the use of reversal agents in direct oral anticoagulant (DOAC) users in Dutch hospitals. Methods A retrospective cohort study was conducted in seven hospitals in the Netherlands. Treatment protocols for bleeding and (urgent) procedures in patients on DOAC were collected from each hospital. All patient data on the use of reversal agents were retrospectively collected from September 2021 to April 2022 and compared to the protocols. The degree of per-protocol adherence (compliance score) was categorized into four levels as follows: poor (<45%), moderate (45–79%), high (80–89%), and full (> 90%) adherence rates. Results A total of 290 patients were included in our study. In patients with bleeding under DOAC, the protocol adherence for prothrombin complex concentrate (PCC) was “moderate” (61%). In the remaining cases (39%), non-adherence was mainly caused by underdosing (68%), overdosing (12%), and a lack of indication (14%). Furthermore, idarucizumab was administered for bleeding with “full” adherence (96%). For andexanet alfa, adherence to the hospital bleeding protocol was “moderate” (67%), with a lack of indication being the only reason for non-adherence. In case of reversal for an urgent procedure, the protocol adherence for PCC was “low” (45%), with underdosing, a lack of indication, and missing lab data being the main reasons for non-adherence. Missing lab data on dabigatran plasma concentration before reversal was the main reason for “low” adherence (26%) in idarucizumab. The adherence for andexanet alfa was also “low” (0%). Conclusion In case of reversal for bleeding under DOAC, overall adherence to the protocol was “moderate”; however, in patients needing an urgent procedure, it was “low.” The major reasons for non-adherence were underdosing, off-label use, and a lack of specific lab testing. The results of this study can assist in improving the implementation of hospital protocols.

ダビガトラン過量服薬に対するイダルシズマブの静脈内投与：血漿中ダビガトラン濃度と血液凝固能の関連性(Intravenous idarucizumab for dabigatran overdose: association between plasma dabigatran concentration and coagulation profile)

要旨ダビガトランは直接トロンビンを阻害することで抗凝固作用を示す経口抗凝固薬であり，近年処方機会が急増している。過量内服症例における，血漿中ダビガトラン濃度および血液凝固能の推移に関するデータは不足している。腎機能障害のない，非弁膜症性心房細動をもつ71歳邦人女性が近医より処方されていたダビガトランを合計7,480mg自殺目的に過量内服し，当院に搬送された。過量内服4時間後の血漿中ダビガトラン濃度は4,217ng/mL（治療域濃度100～400ng/mL）であり，APTTは160.3秒，PT–INRは9.46であった。イダルシズマブ5g経静脈投与後，血漿中ダビガトラン濃度は経時的に低下し，それに伴いAPTTとPT–INRも正常化した。血漿中ダビガトラン濃度とAPTT（R2=0.9898），およびPT–INR（R2=0.9998）との間には強固な関連性が認められた。本症例は第9病日に後遺症なく独歩退院した。治療域の40倍の血漿中濃度を示すダビガトラン大量内服症例において，イダルシズマブは血漿中ダビガトラン濃度を安全に，かつ効果的に低下させた。また，血液凝固能は，血漿中ダビガトラン濃度を強固に反映した。本症例により，一般的な血液凝固能検査を用いることで，ダビガトランの血中薬物動態を推定できる可能性が示された。

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

BackgroundThis study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF).MethodsWe conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up.ResultsEighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (P = 0.013). Our results showed that the CES1 SNP rs8192935 significantly influenced dabigatran trough concentrations in the Chinese population, and carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 SNP c.2482-2236G > A (rs4148738) was associated with major bleeding events in the addictive model (P = 0.046, OR = 3.29) and dominant model (P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435 C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (P = 0.043, OR = 3.34) and dominant model (P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events.ConclusionOur results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.

Preclinical testing of dabigatran in trypsin-dependent pancreatitis.

Pancreatitis, the inflammatory disorder of the pancreas, has no specific therapy. Genetic, biochemical, and animal model studies revealed that trypsin plays a central role in the onset and progression of pancreatitis. Here, we performed biochemical and preclinical mouse experiments to offer proof of concept that orally administered dabigatran etexilate can inhibit pancreatic trypsins and shows therapeutic efficacy in trypsin-dependent pancreatitis. We found that dabigatran competitively inhibited all human and mouse trypsin isoforms (Ki range 10-79 nM) and dabigatran plasma concentrations in mice given oral dabigatran etexilate well exceeded the Ki of trypsin inhibition. In the T7K24R trypsinogen mutant mouse model, a single oral gavage of dabigatran etexilate was effective against cerulein-induced progressive pancreatitis, with a high degree of histological normalization. In contrast, spontaneous pancreatitis in T7D23A mice, which carry a more aggressive trypsinogen mutation, was not ameliorated by dabigatran etexilate, given either as daily gavages or by mixing it with solid chow. Taken together, our observations showed that benzamidine derivatives such as dabigatran are potent trypsin inhibitors and show therapeutic activity against trypsin-dependent pancreatitis in T7K24R mice. Lack of efficacy in T7D23A mice is probably related to the more severe pathology and insufficient drug concentrations in the pancreas.

Thrombolysis after dabigatran reversal: A nation-wide Italian multicentre study, systematic review and meta-analysis.

Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.

Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation. We compared the efficiency of DAB formation from DABE when exposed sequentially to human intestinal and then human hepatic microsomes (mimicking the normal metabolic sequence) with the reverse metabolic sequence in which DABE is exposed to hepatic and then intestinal microsomes. The poor efficiency of DAB formation with reverse sequential hydrolysis indicates that CES2 activity is crucial for active metabolite formation. Thus, the decrease in DAB formation with normal sequential hydrolysis was more sensitive to CES2 inhibition by verapamil (CES2 IC50 = 3.4 μM) than CES1 inhibition by diltiazem (CES2 IC50 = 9.1 μM). These results show CES2 activity plays a crucial role in DAB formation and that variability in its activity is an important determinant of therapeutic response.

Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials.

Background Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children. Objectives This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]). Methods Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ N = 358]; dTT 2,348 [ N = 324]; ECT 2,929 [ N = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure. Results Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children. Conclusion The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran.

Delayed concentration effect models for dabigatran anticoagulation.

IntroductionDabigatran is an anticoagulant with potential use during cardiopulmonary bypass in children and adults. The pharmacokinetic–pharmacodynamic relationship for dabigatran anticoagulation effect was investigated in an intact animal model using rabbits.MethodsTen male New Zealand white rabbits were given a novel preparation of intravenous dabigatran 15 mg.kg−1. Blood samples were collected for activated clotting time, thromboelastometric reaction time, and drug assay at 5, 15, 30, 60, 120, 180, 300, and 420 min. Plasma dabigatran concentrations and coagulation measures were analyzed using an integrated pharmacokinetic–pharmacodynamic model using nonlinear mixed effects. Effects (activated clotting and thromboelastometric reaction times) were described using a sigmoidal EMAX model. Pharmacokinetic parameters were scaled using allometry and standardized to a 70 kg size standard. Pharmacodynamics were investigated using both an effect compartment model and an indirect response (turnover) model.ResultsA two‐compartment model described dabigatran pharmacokinetics with a clearance (CL 0.135 L.min−1.70 kg−1), intercompartment clearance (Q 0.33 L.min−1.70 kg−1), central volume of distribution (V1 12.3 L.70 kg−1), and peripheral volume of distribution (V2 30.1 L.70 kg−1). The effect compartment model estimates for a sigmoid EMAX model with activated clotting time had an effect site concentration (Ce50 20.1 mg.L−1) eliciting half of the maximal effect (EMAX 899 s) and a Hill coefficient (N 0.66). The equilibration half time (T1/2keo) was 1.4 min. Results for the reaction time were plasma concentration (Cp50 65.3 mg.L−1), EMAX 34 min, N 0.80 with a baseline thromboelastometric reaction time of 0.4 min. The equilibration half time (T1/2keo) was 2.04 min.ConclusionsDabigatran reversibly binds to the active site on the thrombin molecule, preventing thrombin‐mediated activation of coagulation factors. The effect compartment model performed slightly better than the turnover model and was able to adequately capture pharmacodynamics for both activated clotting and thromboelastometric reaction times. The equilibration half time was short (<2 min). These data can be used to inform future animal preclinical studies for those undergoing cardiopulmonary bypass. These preclinical data also demonstrate the magnitude of parameter values for a delayed effect compartment model that are applicable to humans.

Dabigatran plasma concentration indicated the risk of patients with non-valvular atrial fibrillation

This study aimed to evaluate the variability of dabigatran plasma concentration and the association with clinical events in Chinese patients treated with dabigatran etexilate (DE) for non-valvular atrial fibrillation (NVAF). The steady-state concentration of dabigatran (the active metabolite of DE) was determined at trough and peak. The effect of dabigatran concentration variability and related factors on clinical outcomes were explored. Data from 86 patients receiving a fixed dose of 110mg showed that dabigatran trough concentration varied remarkably. Age, BMI and history of heart failure were identified as important covariates for dabigatran trough concentration. Dabigatran trough concentration (P = 0.002) and history of hypertension (P = 0.012) scores were identified as key factors for predicting the risk of bleeding events. Dabigatran trough concentration, affected by Age, BMI and history of heart failure, may serve as an independent risk factor for bleeding events in Chinese patients treated with DE for NVAF.

Impact of Idarucizumab and Andexanet Alfa on DOAC Plasma Concentration and ClotPro® Clotting Time: An Ex Vivo Spiking Study in A Cohort of Trauma Patients.

Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell’s viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p < 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p < 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p < 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers’ blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.

What Is The Best Time Sampling For The Two Direct Oral Anticoagulants, Dabigatran and Rivaroxaban?

Introduction Thanks to their predictable pharmacokinetic profile, frequent monitoring of direct oral anticoagulants (DOACs) effects or levels is not recommended in the majority of patients, but it is anticipated that a non-negligible proportion of patients will achieve either insufficient or supra-therapeutic levels of the drug. Moreover, in pharmacokinetic studies with dabigatran etexilate (DE) and rivaroxaban marked interindividual variation in drug levels has been observed. The question about the most appropriate test to assess the treatment response has already been addressed and it was additionally stated that the interval between the drug intake and the blood sampling is mandatory. However, no information regarding the most appropriate delay for monitoring is currently provided. Therefore, the objective of this work is to evaluate the interindividual response at different time points in order to identify which interval between the drug intake and the blood sampling should be preferred for the assessment of the individual response. Methods Series of patients treated with rivaroxaban (AF n=25; VTE n=8) or DE (AF n=18) were included in the study. For each patient, blood was taken at 3 different intervals: - At Ctrough o 22 to 26 hours after the last intake of rivaroxaban o 11 to 13 hours after the last intake of DE - Two hours and three hours after drug administration For rivaroxaban samples, prothrombin time was performed with Triniclot PT Excel S®, RecombiPlasTin 2G® and Innovin®. Rivaroxaban plasma concentration was estimated with the Biophen Direct Factor Xa Inhibitor®. For DE samples, activated Partial Thromboplastin Time (aPTT) was perfomed with STA®-C.K.Prest and SynthasIL®. Plasma dabigatran concentration was estimated with the Hemoclot Thrombin Inhibitor®. Wilcoxon analyses were performed between the different blood sampling intervals. Test for effective pairing was computed with the Spearman non-parametric correlation coefficient with a one-tailed P value. Results Table 1 shows the minimum, the median and the maximum obtained with each tests at each time sampling. [Figure 1][1] provides the box-plot and whiskers (min to max) of the different assays performed on rivaroxaban samples at the different time sampling. [Figure 2][1] provides the box-plot and whiskers (min to max) of the different assays performed on dabigatran samples at the different time sampling. ![Figure 1][2] Figure 1 ![Figure 2][2] Figure 2 Discussion Our results confirm that there is a non-negligible interindividual variation in drug levels at same time points. When comparing intervals, whatever the test used in our study, we can see that results at Ctrough clearly differ from results obtained 2 or 3 hours after the intake of the drug ([Table 1][3]). Interestingly, for rivaroxaban, the median after 2 or 3 hours are closely the same with similar 25th – 75th percentile values whatever the test. Based on our results, we can affirm that for the majority of patients in our study, the Cmax is reached within 2 to 3 hours after the intake. For dabigatran, the plasma concentration is higher at 3h than at 2 hours ([Table 1][3]). However, the power of the study is not sufficient to show a statistically significant effect. Interestingly, this phenomenon is not encountered with the aPTT. This may be due to the well-known flattening curve effect at these higher concentrations. View this table: Table 1 Conclusion Based on our results, we can assert that it seems preferable to take the blood 3 hours after the last intake of DE to avoid missing the Cmax. For rivaroxaban, whatever the blood is taken 2 or 3 hours after the intake, results are similar. Therefore, we recommend to systematically performing blood sampling 3 hours after the intake of the drug to assess the maximal response at these treatments. Sampling at Ctrough is also required to evaluate the clearance. As a limitation, our results should be confirmed in larger cohort studies. Disclosures: No relevant conflicts of interest to declare. [1]: #F1 [2]: pending:yes [3]: #T1

Measurement of Dabigatran Concentration Using Finger Prick Dried Blood Spot Sample Collection

Background and Purpose: Real-world laboratory monitoring of dabigatran activity is challenging. The purpose of the present study was to demonstrate the feasibility and accuracy of finger prick sampling with dried blood spot (fpDBS) cards in measuring the dabigatran concentration. Material and Methods: Patients >20 years of age with atrial fibrillation and receiving dabigatran therapy for more than 7 days were included in the study. Peak and trough dabigatran concentrations were collected by simultaneous finger prick and venous puncture. The dabigatran concentration was measured by ultra-high performance liquid chromatography with tandem mass spectrometry. Our previously developed post-column infused internal standard (PCI-IS) method was applied to estimate the blood spot volume on fpDBS and to calibrate the drug concentration. Deming regression was used to analyze the correlation between dabigatran concentration on fpDBS cards and in plasma samples, followed by Bland–Altman analysis to compare the bias between two sampling techniques. Results: A total of 33 patients were enrolled and contributed 66 plasma and 55 fpDBS dabigatran samples. The average patient age was 74.6 ± 7.9 years, mean creatinine clearance 58.1 ± 18.3 mL/min, and CHA2DS2-VASc score 3.5 ± 1.6 points. The dabigatran concentration ranged from 41.8–1421.7 ng/mL. The plasma and DBS dabigatran concentrations correlated well (r = 0.98), and the conversion factor for fpDBS to plasma dabigatran concentration was 1.28. The Bland–Altman analysis showed that 94.5% of the fpDBS-predicted concentration fell within 20% of bias. Conclusions: The study showed that fpDBS measurement of dabigatran concentration is reliable and can be applied in clinical scenarios.

An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in &lt; 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

Viscoelastometry for detecting oral anticoagulants

BackgroundDetermination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device.MethodsThis prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test).Results70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors.ConclusionsIn emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking.Trial registrationGerman clinical trials database ID: DRKS00015302.

Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy

We present a case of patient with spontaneous cardiac tamponade related to a very high 2-plasma concentration of dabigatran, an oral direct-acting thrombin inhibitor. By selectively inhibiting thrombin alone, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. Nonetheless, serious bleeding can occur with dabigatran. We illustrate the management of this life threatening hemorrhagic complication by the combination of cardiac surgery, antagonization of the anticoagulant effect (using Idarucizumab, an humanized monoclonal antibody fragment and continuous renal replacement therapy), and monitoring of the effects on coagulation by thromboelastogram.