Dabigatran Trough Research Articles

Biological Variation of Hemostasis Analytes in Atrial Fibrillation Patients Using Dabigatran.

Analytical criteria for laboratory analysis based on biological variation are considered state-of-the-art. While biological variance should ideally be measured in patient populations for whom the tests are relevant, data are mostly only available from healthy individuals. We determined the biological variance of activated partial thromboplasmin time (APTT), prothrombin time (PT), fibrinogen, and trough dabigatran levels in patients with atrial fibrillation (AF) who were treated with dabigatran. Between 2019 and 2022, patients with AF treated >3 months with dabigatran were included. Blood was collected monthly up to 10 times for the measurement of APTT, PT, fibrinogen, and trough dabigatran levels. Between-subject variance (CVG), within-subject variance (CVI), and analytical variance (CVA) were calculated. Eighteen participants (median age 65.8 years, 22.2% women) were included, with 130 samples in total. For APTT, the CVG was 11.5%, the CVI 8.8%, and the CVA 1.1%. For PT, these values were 5.2%, 4.0%, and 1.0% and for fibrinogen 13.6%, 11.8%, and 1.6%, respectively. For the dabigatran levels, the percentages were 37.9%, 33.0%, and 3.4%, respectively. We assessed the biological variance of APTT, PT, fibrinogen, and dabigatran in a patient population with long-term dabigatran use. The analytical performances of coagulation laboratory tests in patients with AF treated with dabigatran were comparable to those in healthy volunteers.CCMO Registration Number: NL67304.078.18.

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.

A Review of Pharmacogenetics of Anticoagulant Therapy

Variances in the patients’ outcomes have been a well-documented challenge in anticoagulant therapy. A clinical encounter with a thromboembolic or a hemorrhagic event, due to subtherapeutic or adverse effects of an anticoagulant, is often managed by switching the anticoagulant agent into another, which is more specific and direct-acting. This management approach is usually associated with a financial burden. Additionally, the certainty of achieving better efficacy and safety profile is still questionable. Genetic variants affecting the protein sites that are involved in the anticoagulant pharmacokinetic and pharmacodynamics interactions have been suggested to contribute to the variability in the response to anticoagulant therapy. The current work reviewed the studies investigating the response variability associated with the anticoagulant therapy (heparins, rivaroxaban, apixaban, and dabigatran) and the potential pharmacogenes contributing to such response variability. Several genetic polymorphisms were reported as potential contributors to variances in response to anticoagulant therapy and were associated with adverse events. A link has been proposed for heparin resistance with single nucleotide polymorphisms (SNPs) of the anti-thrombin-encoding gene (SERPINC1) as well as heparin-induced thrombocytopenia with human leukocyte antigen (HLA) variant allele (HLA-DRB3*01:01). Several investigations also remarked variations in the serum drug level of direct oral anticoagulants (DOACs) that are associated with SNPs in the proteins contributing to the pharmacokinetics of the anticoagulant agent. Several studies discerned significant associations between SNPs in the ABCB1 gene and elevations in the serum levels of rivaroxaban, apixaban, and dabigatran. Moreover, carriers of the variant genotype of the SNP (rs776746) in the cytochrome P450 3A5 enzyme-encoding gene (CYP3A5) had significantly higher drug levels when compared with the non-carriers. In contrast, some SNPs were reported to impart a protective phenotype to the carrier. The SNP (rs2244613) in the carboxylesterase-encoding gene (CES1) has been significantly associated with a decline in dabigatran trough levels and a lower risk of hemorrhage. Further investigations are essential to elucidate the extent of pharmacogenetics-based alterations in the drug levels as well as the subsequent clinical outcomes of anticoagulant therapy.

A systematic review and meta-analysis of dabigatran peak and trough concentration in adults.

Dabigatran etexilate is an oral direct thrombin inhibitor used in preventing thromboembolism in patients with atrial fibrillation and several other conditions. Routine dabigatran concentration monitoring is not recommended in clinical practice; however, measurement of dabigatran concentration may be required in several conditions. This study aims to pool the peak and trough dabigatran concentration from real-world studies. A systematic review was performed to identify studies that measured the peak and trough dabigatran concentrations. Observational studies reporting dabigatran peak or trough concentrations and patients' clinical characteristics of either sex, age or weight were included. Random-effect meta-analyses and metaregression were conducted to pool dabigatran concentrations and to identify the correlation between factors affecting dabigatran concentrations. Fifteen studies with a total of 1226 patients were included. The pooled peak dabigatran concentration was 133 ng/mL (95% CI: 113-154, I2 = 86%, n =655), while the pooled dabigatran trough concentration was 80 ng/mL (95% CI: 69-91, I2 = 93%, n =1010). Metaregression analyses suggested that age is significantly correlated to trough concentration, while body weight and creatinine clearance significantly correlated to peak concentration. Subgroup results revealed that dabigatran concentration when measured with liquid chromatography-tandem mass spectrometry was higher than haemoclot thrombin inhibitor assay. Several guidelines have proposed dabigatran concentrations target range and the pooled dabigatran concentrations were in line with the suggested range. Further studies to correlate dabigatran concentrations and clinical outcomes is warranted to improve the safety and efficacy monitoring of dabigatran therapy.

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.

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Dabigatran trough concentrations in very elderly patients

ObjectivesThe aim of this observational study was to explore dabigatran concentrations in elderly and very elderly patients in a real-life population. Patients aged >75 years receiving dabigatran have a significantly...

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.

The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study.

Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease.

Background Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration. Methods Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Results A total of 96 patients aged 51-89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m2, p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients. Conclusions Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.

Safety of dabigatran in patients with atrial fibrillation and chronic kidney disease: pharmacokinetic and pharmacogenetic aspects

Background: despite well-studied safety profile of dabigatran its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). This study was aimed to evaluate relationships between CES1 and ABCB1 polymorphism, dabigatran trough plasma concentration (DTPC) and bleeding events in patients with AF and CKD.Methods: patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110mg or 150 mg have been included in the study. Real-time PCR was used to evaluate single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs1045642, rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.Results: a total of 60 patients, aged 51–89 years (median age 76 years) were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p &lt; 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). We found C/D values to have high interindividual variability (mean 365.9 ± 290.4 μg/ml: mg/day, range 23.64-1452.73). Individuals with CKD 3B had higher concentration of dabigatran compared with those with 3A stage (488.7 ± 232.3 vs 332 ± 297.8 μg/ml : mg/day, p = 0.02). Consequently, there also was negative correlation of C/D with CrCl (r = -0.4, p = 0.0015). Evaluated SNPs (rs1045642, rs4148738, and rs2244613) did not affect C/D values (H test p &gt; 0.05).Conclusions: C/D values were significantly higher in patients with CKD 3B stage and those treated with dabigatran 110 mg. There was no influence of aforementioned SNPs on dabigatran trough concentrations and clinical outcomes.

The Impact of Proton Pump Inhibition on Dabigatran Levels in Patients With Atrial Fibrillation.

Proton pump inhibition (PPI) administrated together with dabigatran reduces the risk of gastrointestinal hemorrhage. However, there is a discussion regarding possible PPI-dabigatran interaction that may reduce the efficacy of this therapy. To determine the impact of concomitant PPI on dabigatran plasma levels in patients with nonvalvular atrial fibrillation (NV-AF). A pilot prospective study in patients with NV-AF on dabigatran therapy was performed; 31 patients were enrolled. PPI with either omeprazole or pantoprazole was administrated in 19 patients. Blood samples were taken for the assessment of the dabigatran trough and peak levels. Dabigatran concentration was measured with the Hemoclot Thrombin Inhibitor Assay. There were significant differences in dabigatran trough level comparing patients treated with PPI and patients without PPI (58.86 ± 36.76 ng/mL vs. 110.72 ± 88.47 ng/mL, P < 0.05). Similarly, there were significant differences in dabigatran peak level between compared groups (88.0 ± 20.5 ng/mL vs. 174.4 ± 139.64 ng/mL, P < 0.05). This pilot study demonstrated the interaction between PPI and dabigatran levels in patients with NV-AF.

Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.

Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P‐glycoprotein inhibitor. Because the combined effects of drug–drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P‐glycoprotein inhibitors is empirical at its best. We conducted virtual drug–drug interactions studies between DABE and the P‐glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population‐based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug–drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies.

Dabigatran Levels in Elderly Patients with Atrial Fibrillation: First Post-Marketing Experiences.

The number of elderly individuals with non-valvular atrial fibrillation (NV-AF) requiring long-term anticoagulation is rising. The pharmacokinetics of oral anticoagulants in elderly individuals may differ from that for younger patients. The aim of this study was to assess the dabigatran levels in elderly patients with NV-AF. A pilot prospective post-marketing study in patients with NV-AF on dabigatran therapy was performed; we enrolled 21 consecutive elderly patients (aged ≥ 75years) on a reduced dabigatran regimen (110mg twice daily) and compared them with 13 younger (≤ 70years) individuals on reduced dabigatran therapy due to renal impairment and with 16 younger patients on standard dabigatran therapy (150mg twice daily). Blood samples were taken for the assessment of dabigatran trough and peak levels. Dabigatran levels were measured with the Hemoclot® Thrombin Inhibitor Assay. There were significant differences in dabigatran trough levels when comparing elderly patients on reduced dabigatran with non-elderly patients on reduced dabigatran (99.3 ± 73.6 vs 51.6 ± 25.6ng/mL; p < 0.01). Similarly, the detected dabigatran peak levels were significantly higher in elderly patients on reduced dabigatran compared with non-elderly patients on reduced dabigatran (173.4 ± 116.2 vs 116.1 ± 19.1ng/mL; p < 0.01). No significant differences in dabigatran trough and peak levels were found when comparing elderly patients on reduced dabigatran with non-elderly patients on standard dabigatran therapy. This pilot study demonstrated that elderly patients on reduced dabigatran exhibit significantly higher dabigatran levels than younger individuals on a reduced regimen, and similar levels compared with younger individuals on standard dabigatran.

Real-Life Peak and Trough Dabigatran Plasma Measurements over Time in Hospitalized Geriatric Patients with Atrial Fibrillation.

Few geriatric patients were included in studies on direct oral anticoagulants and data on dabigatran concentration and safety are needed in this population. Our objectives were to evaluate peak and trough dabigatran plasma concentrations over time in a geriatric population and to identify factors associated with dabigatran plasma concentrations and to assess the relationship with bleeding events. Peak and trough dabigatran plasma concentration were performed 4,8,15,30,45 days after inception of dabigatran treatment in 68 consecutive patients ≥75 years old hospitalized in a geriatric hospital with atrial fibrillation. Bleeding events were monitored for 1 year. Mean age was 85.8(5.1) years old and 76.5% were women. Overall, 541 dabigatran plasma measurements (270 peak, 271 trough) were performed. Mean dabigatran concentrations of the 5 sequential measurements ranged 106-146ng/mL for peak and 66-84ng/mL for trough. Renal failure was associated with high peak and trough dabigatran concentration. Inter- and intra-individual coefficients of variation were 59.5% and 44.7% for peak and 74.5% and 44.6% for trough. Participants in the lower two tertiles of dabigatran concentration at day 8 (D8) remained below the 90th percentile (243.9ng/ml) on the next measurements. Bleeding events were associated with high trough dabigatran concentrations. Trough dabigatran concentration at D8>243.9ng/mL significantly predicted bleeding. In this geriatric population, renal function and low albumin were associated with dabigatran concentrations. Despite large variability, participants in the lower two tertiles of dabigatran concentration at D8 remained below the 90th percentile on the following measurements. D8 dabigatran trough concentration≥243.9ng/mL identified patients at risk of bleeding.

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability

Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non-linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.

PHARMACOGENETIC ASPECTS OF NEW ORAL ANTICOAGULANTS APPLICATION

The aim of this review is to assess the effect of genetic factors on the pharmacokinetic parameters of new oral anticoagulants. The review presents data from studies investigating the effect of gene polymorphisms that encode biotransformation enzymes and transporter proteins of new oral anticoagulants on the pharmacokinetics of these drugs. RE-LY study showed a 15% decrease in trough dabigatran concentration and 27% lower risk of bleeding in carriers of CES1 gene rs2244613 polymorphism, there was also a tendency to reduce the risk of major bleeding. Further study of CES1 gene rs8192935 polymorphism showed a 3% decrease in trough dabigatran concentration in heterozygotes and 11% in homozygotes. There was found a 2% and 3% decrease in trough concentrations in hetero- and homozygotes for the minor allele of CES1 gene rs2244613 polymorphism, respectively. There was no significant effect of ABCB1 gene rs2032582 and rs1045642 polymorphisms on dabigatran pharmacokinetics. It is known the case of gastrointestinal bleeding in the carrier of allelic variants of ABCB1 gene rs2032582 and rs1045642 polymorphisms. However, there was no significant effect of genotype on rivaroxaban pharmacokinetics in the study involving the carriers of ABCB1 gene rs2032582 and rs1045642 polymorphisms. ABCB1 gene rs4148738 polymorphism was associated with higher apixaban peak concentration. But groups of patients with acute cardioembolic stroke showed no statistically significant difference of apixaban peak concentration depending on ABCB1 gene rs1045642 polymorphism genotype. ABCB1 gene rs1045642 and SLCO1B1 gene rs4149056 polymorphisms have no effect on edoxaban pharmacokinetics. Elevation of edoxaban metabolite concentration in carriers of SLCO1B1 gene allelic variants was not clinically significant because the proportion of metabolite is about 10% of the concentration of the main substance. It is necessary to provide large population studies with control of treatment efficacy and safety to prove clinical significance of genotyping for new oral anticoagulants use.

Pharmacokinetics (PK) and Pharmacodynamics (PD), Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Etexilate Given after Standard Anticoagulant Therapy in Children from Birth to Less Than One Year Old, with Venous Thromboembolism

Background: Venous thromboembolism (VTE) events are more frequent in neonates than in children of other age groups. The standard of care for pediatric anticoagulation includes unfractionated or low-molecular-weight heparin, or vitamin K antagonists. However, these treatments have limitations in terms of practicality of use in infants, such as parenteral administration, frequent monitoring and drug interactions. Alternative oral agents that address these shortcomings may improve compliance, efficacy and safety. The safety and efficacy of dabigatran etexilate (DE), a direct thrombin inhibitor, are established in adults; pharmacokinetic/pharmacodynamic (PK/PD) studies indicate linear PK. There is a relationship between dabigatran plasma concentration (PK) and its PD effects, resulting in reproducible dose-dependent prolongation in clotting times with rapid onset and offset of effect, which is consistent across populations. Although phase IIa studies suggest a similar PK/PD relationship of dabigatran in children and adults, the hemostatic system in infants differs from older children and adults, which may lead to a different PK/PD effect.Objective: To demonstrate comparable PK/PD relationship of DE oral liquid formulation (OLF) between infants and older children and adults, and to assess safety and tolerability.Methods: Open-label, multicenter, single-dose, single-arm, phase IIa pediatric study. Infants aged < 1 year diagnosed with VTE who completed standard anticoagulant treatment for VTE were enrolled. Exclusion criteria included < 37 weeks gestational age at birth, weight < 3 kg, major bleed with standard anticoagulant and swallowing abnormalities. Patients received DE OLF (based on age- and weight-adjusted nomogram) and were followed up for 30 (+7) days. The primary endpoints were PK/PD related, measured at 2 hrs and 12 (±2) hrs after DE administration. The PK endpoint was plasma concentration of total dabigatran, and PD endpoints were activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Secondary endpoints included incidence of all bleeding events and adverse events (AEs), acceptability and tolerability. Descriptive statistics were applied to the endpoints. PK/PD relationship was analyzed using a simple linear regression model and nonlinear Emax model to confirm whether models used in previous studies were consistent with the pediatric data of this study.Results: Ten patients were screened and 8 entered the study (mean age [SD]: 89 [52] days; range: 41-169 days). Patients received a single dose of DE OLF. The geometric mean (gMean) total dabigatran plasma concentrations 2 hrs post dose (around peak concentrations) was 120 ng/mL with geometric coefficient of variation (gCV) of 62.1%, which indicated moderate variability. The gMean at 12 hrs post dosing was 60.4 ng/mL (gCV 30%), which indicated low variability. The projected steady-state dabigatran trough concentrations were largely comparable to those observed in adults with VTE (Table).A linear PK/PD relationship was observed for ECT (ECT ratio) and dTT (dTT ratio) (Figure). The relationship between total dabigatran concentration and aPTT (aPTT ratio) was nonlinear. The observed PK/PD relationships were similar to those in adult and adolescent patients with VTE, except for patients aged < 2 months, in whom a slight upward shift of aPTT of 10-20% (average) and ECT by 10-15% was observed relative to adults. There were no AEs, deaths or treatment discontinuations during the treatment period. None of the treated patients had any bleeding events or thromboembolic events during the study. One patient had a serious AE (aortic stenosis) during the post-treatment period, which was not considered treatment related by the investigator. There were no clinically relevant or unexpected laboratory findings. The majority of patients were assessed with good tolerability (six patients, 75%), and one patient each (12.5%) was evaluated with satisfactory or bad tolerability.Conclusion:In this small population of infants (aged < 1 year), DE OLF was well tolerated without any treatment-related AEs, thromboembolic or bleeding events. The observed PK/PD relationships were consistent with the established profile in adult and adolescent patients with VTE. [Display omitted] [Display omitted] DisclosuresHalton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim. Picard:Boehringer Ingelheim: Employment. Harper:Boehringer Ingelheim: Employment. Huang:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Maas:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Nurmeev:Boehringer Ingelheim: Other: Investigator fees. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Given after Standard Anticoagulant Therapy in Children (Two Age Groups: 1-

Background:The incidence of venous thromboembolism (VTE) in children is increasing. The current standard of care is unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and Vitamin K antagonists (VKAs), all of which have limitations. Dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE), is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard care.Objective:The objectives of this phase IIa study were to obtain pharmacokinetic (PK) and pharmacodynamic (PD) data and to evaluate the tolerability and safety of an oral liquid formulation (OLF) of DE in patients aged 1 to < 12 years.Methods:The open-label, multinational, multicenter, non-randomized, single-arm study was conducted in patients aged 1 to < 2 years and 2 to < 12 years with a diagnosis of VTE, who had completed planned treatment with LMWH or oral anticoagulants (VKAs) for VTE.DE was administered as an OLF at a weight and age-adjusted dose (calculated using a nomogram) equivalent to 150 mg twice daily (bid) in adults. Originally, all patients were to receive multiple dosing (bid for 3 days). However, this was replaced with single dosing (SD) in the course of the study. A 30-day follow-up was included. Here we report data from SD patients only.The primary PK endpoints were plasma concentration of total dabigatran, free dabigatran, unchanged DE and intermediate metabolites. To compare the exposure to DE in pediatrics with that in adults with VTE, gMean concentrations at 10 hours after SD of DE were extrapolated to steady-state trough concentration. An accumulation ratio was calculated based on the terminal half-life (t1/2) and the dosing interval (for a bid dosing regimen) to project the steady-state dabigatran plasma concentration. Primary PD endpoints were activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and diluted thrombin time (dTT). Primary safety endpoints were incidence of all bleeding events and incidence of all adverse events (AEs).Results:Six patients aged 1 to < 2 years and 9 patients aged 2 to < 12 years received SD DE; 3 patients aged 2 to < 12 received multiple doses (bid for 3 days).In the SD groups, plasma concentration of total dabigatran increased at 2 hours (peak) after dosing then decreased until 10 hours after dosing. The projected steady-state dabigatran trough concentrations of both age groups of children studied were largely comparable to those observed in adults with VTE, i.e. the projected results for children fell between the first and the third quartile of adult trough concentrations (Table).Data from the SD groups indicated that there was a linear PK/PD relationship for ECT and dTT (see Figure) and a non-linear PK/PD relationship for aPTT. The PK/PD relationships were similar to those seen in adults (for all coagulation parameters analyzed) and adolescents (dTT and ECT) with VTE.During the on-treatment period there were no study drug related AEs; one patient had AEs (leukopenia and dizziness), which were mild in intensity and unrelated to the study drug. No AEs were reported during the post-treatment or post-study periods. No bleeding events were reported.Conclusion:The OLF of DE was well tolerated in pediatrics, with no drug-related AEs or bleeding events. Projected steady-state dabigatran trough concentrations were largely comparable to those seen in adults with VTE. The observed PK/PD relationship was similar to that seen in adults and adolescents with VTE. [Display omitted] [Display omitted] DisclosuresHalton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Luciani:Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Huang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Maas:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy.

Rationale and Design of a Phase III Single-Arm Multicenter Study of Dabigatran Etexilate for the Secondary Prevention of Venous Thromboembolism in Children

Background: In children, the incidence of venous thromboembolism (VTE) is increasing and is often associated with underlying diseases such as cancer, or risk factors such as thrombophilia. Following treatment for acute VTE, thrombosis or thromboembolic events can recur particularly if a clinical risk factor for VTE persists. The efficacy and safety of the oral anticoagulant dabigatran etexilate (DE) have been demonstrated in a number of thrombosis-related indications in adults, including for secondary VTE-prevention. There are, however, potential differences between adults and children related to developmental physiology and pharmacology and therefore trials to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of DE in children are required. To date, all pediatric phase IIa studies conducted have shown a similar PK and PK/PD relationship of DE in comparison to adult studies.Objective: To describe the design of a study to evaluate the safety and PK-PD of DE for secondary prevention of VTE in children aged 0-<18 years.Methods: This phase III, open-label, single-arm, multicenter study will be conducted at ~100 sites worldwide (NCT02197416). Eligible patients will have completed a course of initial treatment for confirmed acute VTE (for ≥ 3 months) and be considered at high risk for VTE recurrence due to the remaining presence of a clinical risk factor. Approximately 100 subjects between 0-<18 years of age will be included. Treatment with DE will extend up to 12 months, or less if the clinical risk factor resolves, with a follow-up visit 28 days after the last dose. DE will be administered twice daily as capsules, pellets or oral liquid formulation, depending on subject age and their ability to swallow capsules or pellets. A dosing nomogram will be used to scale down an adult dose based on the child’s age and weight. Initial doses calculated using the nomogram should achieve steady-state trough concentrations of DE of between 50 and < 250 ng/ml, a range which is assumed to result in safe and effective use of DE in this pediatric population; after about 3 days, trough dabigatran plasma concentration will be measured and DE may be titrated up or down to achieve the target steady-state trough plasma concentration.Results: Demographic and medical history data will be collected for all participants. The primary outcomes to be evaluated are instances at 6 and 12 months of image-proven VTE recurrence; major and minor bleeding, including clinically relevant non-major bleeding; and overall and thrombotic/thromboembolic mortality. All elements of the primary endpoints will be evaluated by an independent adjudication committee that will confirm or refute outcome events. The secondary outcomes are rates of post-thrombotic syndrome at 6 and 12 months; PK and PD (e.g., activated partial thromboplastin time and ecarin clotting time); and the number of DE dose adjustments required during the treatment period. Data on the acceptability of the age-appropriate drug formulation, the tolerability of the study medication, adverse events, treatment discontinuations due to an adverse event, and laboratory and clinical parameters will also be collected during the study. Safety and tolerability will be monitored by the independent Data Monitoring Committee.Conclusion: This phase III study has been designed to provide data on the safety and PK-PD of DE for the secondary prevention of VTE in children aged 0-<18 years. DisclosuresLuciani:Boehringer Ingelheim: Other: Member of Pediatric Expert Working Group for Boehringer Ingelheim. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Mitchell:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Huang:Boehringer Ingelheim: Employment. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.