Dataset Information

Determination of Dabigatran Concentration in Human Plasma and Breast Milk.

ABSTRACT: Venous thromboembolism (VTE) is an important cause of death following childbirth. Dabigatran etexilate can be a useful prophylaxis in susceptible women during the postpartum period. However, it is not clear whether dabigatran is excreted into breast milk in amounts which can be harmful to the suckling baby. We have developed an accurate, sensitive, and specific assay for the quantitation of dabigatran in both human plasma and breast milk. This is particularly useful for the determination of the extent by which dabigatran is secreted into breast milk in relation to its systemic availability. Dabigatran was enriched from both matrices using solid-phase extraction prior to separation on a C8-RPLC column and detection using SRM on a QqTrap mass spectrometer. The assay was validated for specificity, sensitivity, linearity, precision, accuracy, and stability of the analyte in human plasma and breast milk. The lower limit of detection for dabigatran was 20 pg/ml in plasma and 75 pg/ml in breast milk. This assay will aid future studies for the measurement of dabigatran concentrations in human breast milk to help determine if dabigatran etexilate can safely be administered to breast-feeding women.

SUBMITTER: Sidgwick F

PROVIDER: S-EPMC8556115 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Determination of Dabigatran Concentration in Human Plasma and Breast Milk.

Sidgwick F F Porter A A Ayuk P P Kamali F F Truemann A A

International journal of analytical chemistry 20211022

Venous thromboembolism (VTE) is an important cause of death following childbirth. Dabigatran etexilate can be a useful prophylaxis in susceptible women during the postpartum period. However, it is not clear whether dabigatran is excreted into breast milk in amounts which can be harmful to the suckling baby. We have developed an accurate, sensitive, and specific assay for the quantitation of dabigatran in both human plasma and breast milk. This is particularly useful for the determination of the ...[more]

PMID: 34721581

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Project description: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 (T1/2 keo) 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 (T1/2 keo) 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.

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Dataset Information

Determination of Dabigatran Concentration in Human Plasma and Breast Milk.

Publications

Determination of Dabigatran Concentration in Human Plasma and Breast Milk.

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