Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study
Dagmar KubitzaStefan WillmannMichael BeckaKirstin ThelenGuy YoungLeonardo R. BrandãoPaul MonagleChristoph MaleAnthony K.C. ChanGili KennetIda MartinelliPaola SaraccoAnthonie W.A. Lensing
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The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.ClinicalTrials.gov number, NCT01145859.Keywords:
Pharmacodynamics
Prothrombin time
Angiology
Prothrombin time
Thromboplastin
Coagulation testing
Activated clotting time
Clotting time
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A prospective, randomized trial is described in which the usefulness of two tests in the control of anticoagulant therapy is compared. Fifty-two patients were controlled by the one-stage prothrombin time and 55 by the activated partial thromboplastin time. There was no significant difference in the incidence of bleeding between the two groups. When bleeding did occur, it was more often reflected by prolongation of the prothrombin time than of the activated partial thromboplastin time. The prothrombin time was found to have some practical advantages over the activated partial thromboplastin time.
Prothrombin time
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Anticoagulant Therapy
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<p class="abstract"><strong>Background:</strong> Prothrombin time (PT) and activated partial thromboplastin time (APTT) are tests of haemostasis commonly employed in the evaluation of coagulopathies. Storage temperature and time interval between sample collection and testing can have a significant effect on results of coagulation tests. The aims of the study were investigate whether storage temperature and time influence the results of routine coagulation tests and whether any changes caused by delayed analysis results in a clinically relevant difference, as well as to establish our own acceptable storage temperature and time guidelines.</p><p class="abstract"><strong>Methods:</strong> This study was conducted at Department of Clinical Haematology, in a tertiary care center in Kashmir valley. This study included 50 cases. Individuals with chronic liver diseases or cardiovascular disorders, subjects on anticoagulant therapy were excluded. 25 samples were observed at room temperature (RT) and 25 samples at 2-8°C. PT and APTT was measured at 0, 2, 4, 8, 16 and 24 hours both at RT and 2-8°C. Findings at 0 hr were compared to findings at 2,4, 8,16 and 24 hours in both the groups. </p><p class="abstract"><strong>Results:</strong> In case of PT, reliable results were obtained up to 24 hrs either kept at RT or at 2 to 8°C and for APTT reliable results were obtained up to 4 hours kept at RT or at 2 to 8°C as there was no significant change during this period.</p><p class="abstract"><strong>Conclusions:</strong> Coagulation test should be performed as soon as possible with PT being performed before 24 hours and APTT before 4 hours of collection of sample irrespective of whether the sample has been preserved at RT or in refrigerator.</p>
Prothrombin time
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Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are routine coagulation tests. The absence of age-dependent reference interval (RI) may lead to abnormal results in children. In this study, we aimed to verify adult-based RIs in children and establish pediatric RIs for PT and aPTT.We analyzed PT and aPTT results. Samples from inpatients and outpatients aged 1 - 18 years, considered healthy subjects, were divided into six groups by age. Verification and establishment of RIs were conducted.Applying adult-based RIs to pediatrics was statistically invalid for individuals aged 10 - 18 years for PT and invalid throughout childhood for aPTT. The new RI of PT for individuals aged 10 - 18 years was 11.1 - 14.1 seconds and that of aPTT for individuals aged 1 - 9 years was 28.2 - 46.0 seconds.Pediatric RIs were higher than adult-based RIs. Using pediatric RI can save time, labor, and costs to make clinical decision.
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Patients with severe acne may need elective/urgent surgical interventions during treatment with isotretinoin and it is critical for the surgeon to consider the possible effects of this medication on coagulation systems. The aim of this study is to determine the changes in prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) during isotretinoin treatment. PT, aPTT, and INR values of 51 severe acne patients were evaluated during routine pre-treatment biochemical analysis. Only patients with normal values were included in the study. The results of before and after 1 month treatment were compared statistically. There were no statistically significant change in mean alanine aminotranferease (ALT), aspartate aminotransferase (AST), PT, and INR values after treatment. A significant increase in aPTT was detected. The INR values, which are more trusted and safe, showed no difference. Isotretinoin seems to have no effect on these coagulation parameters.
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Isotretinoin
Coagulation testing
Alanine aminotransferase
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Objectives To assess the reliability of prothrombin time and activated partial thromboplastin time results generated from citrated whole blood samples following short‐term storage at room temperature. Methods Clotting times were measured in blood samples from 40 dogs that showed a variety of clinical signs. Before measurement of prothrombin time and activated partial thromboplastin time in citrated plasma, whole blood samples were split in three aliquots; one was processed within 30 minutes of collection (fresh) while the remaining two were stored unseparated at room temperature for 24 ( 24RT ) or 48 ( 48RT ) hours. Results The median prothrombin time for the 24RT (7 seconds) and 48RT (7·2 seconds) samples were not significantly different to those obtained from the fresh (7·1 seconds) samples but the median activated partial thromboplastin time for the 24RT (12·6 seconds) and 48RT (12 seconds) samples were significantly shorter than those obtained from the fresh samples (14·2 seconds). Clinical Significance Storage of citrated whole blood at room temperature for 24 or 48 hours did not significantly alter the measurement of prothrombin time but resulted in significantly shorter activated partial thromboplastin time results. Extrapolating from these findings, it is proposed that unseparated clinical samples that are submitted to an external diagnostic laboratory for the performance of clotting times, may generate reliable prothrombin time but unreliable activated partial thromboplastin time results.
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Thromboplastin
Activated clotting time
Clotting time
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The results of determinations of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are frequently used to assess hemostatic function. Accurate results for these laboratory tests depend on many variables, one of which is the ratio of plasma to anticoagulant. We studied 12 patients and 4 normal subjects to determine the effects of sample volume on PT and aPTT. We conclude that underfilling may produce profound effects, particularly on the aPTT. In contrast, overfilling rarely affects the results. The greatest effects of sample volume were observed in specimens in which the true PT or aPTT was elevated. A normal PT or aPTT result on any specimen, regardless of sample volume, strongly suggests that the true value is normal.
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Objective To investigate the effect of storage time on prothrombin time(PT) and activated partial thromboplastin time(APTT) at room temperature under the condition of coagulation disorder.Methods Clinical specimens with normal and prolonged storage time on PT and APTT tests were enrolled.The assay was conducted immediately after centrifuge,and PT of 11.0-14.3 s and APTT of 32.0-43.0 s were considered as the normal range.The specimens were kept at room temperature,and the coagulation test was performed at 1 h,2 h,4 h,6 h,8 h,12 h,24 h after collection.Results For normal specimens,PT result was stable up to 8 h,APTT up to 4 h at room temperature;but for the prolonged storage time,PT was stable up to 4 h,APTT 2 h.Conclusion Normal specimens were stable at 4 h for coagulation tests,but the coagulation assays should be performed in 2 h for the prolonged group was stable for only 2 h.
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Coagulation testing
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Clotting time
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During orthotopic liver transplanatation haemostasis is often disturbed and coagulation monitoring is mandatory. We compared the results obtained by whole blood prothrombin time and activated partial thromboplastin time assays (Hemochron) and thrombelastometry (ROTEM) 05) with laboratory coagulation assays (prothrombin time, activated partial prothrombin time, fibrinogen, and platelet count) in samples obtained during orthotopic liver transplantations. Determination of prothrombin time and activated partial prothrombin time using the Hemochron device showed good correlation with laboratory coagulation assays (r = 0.912, p < 0.001, and r = 0.794, p < 0.001). Maximum clot firmness as determined by thrombelastometry correlated well with platelet count (r = 0.779, p < 0.001) and, to a lesser degree, with fibrinogen concentration (r = 0.590, p < 0.001). During orthotopic liver transplantation, prothrombin time and activated partial prothrombin time can be reliably determined by the Hemochron device, while thrombelastometry allows assessment of platelet count and fibrinogen concentration.
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Objective:To investigate the influence to the results of prothrombin time(PT) and activated partial thromboplastin time(APTT) causing by different volumes of clinical blood collection.Methods:The PT and APTT of 15 patients were assayed,respectively,by the BE-RockRotor instrument using different volumes of clinical blood collection and the data were analyzed statistically.Results:The results of PT and APTT which the volumes of clinical blood collection were 1.8 mL or 1.8 mL were different significantly in statistics to those which the volumes were accurate.Conclusion:The results of PT and APTT were influenced by the volumes of clinical blood collection.So using the standard blood collection procedure for blood clotting system determining is necessary and can offer the accurate results for clinical diagnosis.
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Blood collection
Thrombin time
Thromboplastin
Activated clotting time
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