Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children's Oncology Group.

SevenChildren's Oncology Group phase 2 trials for patients with relapsed/progressive solid tumors were analyzed to estimate the event-free survival (EFS) for relapsed/progressive Ewing sarcoma. One hundred twenty-eight Ewing sarcoma patients were enrolled and 124 events occurred. The 6-month EFS was 12.7%, demonstrating the poor outcome of these patients. Only docetaxel achieved its protocol-specified radiographic response rate for activity; however, the EFS for docetaxel was similar to other agents, indicating that a higher radiographic response rate may not translate into superior disease control. This EFS benchmark could be utilized as an additional endpoint in trials for recurrent Ewing sarcoma.

Prospective trial of a pediatric ventricular assist device.

BACKGROUND: Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS: We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS: For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS: Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

Response to warfarin therapy in obese pediatric patients dosed according to institutional guidelines.

BACKGROUND: Current warfarin dosing guidelines for pediatric patients do not account for obesity. Published data from adults suggest that obesity may affect warfarin dosing requirements. Obesity is prevalent in the pediatric population, and current warfarin dosing methods should be evaluated in obese pediatric patients. METHODS: Patients aged 2 to 18 years who were obese and initiated on warfarin therapy at our institution as inpatients from 2004 to 2010 were identified and matched in a 1:2 ratio by age and sex with nonobese patients who were initiated on warfarin therapy. Patients were categorized obese per Centers for Disease Control guidelines. Demographic and disease state information, warfarin dosing information, INR values, and interacting medications were collected. Warfarin was dosed according to the institutional guidelines adapted from the published literature. Time to therapeutic INR value was the primary endpoint and percent of patients with supratherapeutic INR values was the secondary endpoint. RESULTS: A total of 30 patients met the study criteria (10 obese, 20 nonobese), and baseline demographic variables were similar. No significant differences were noted in the number of INR values drawn, number of warfarin doses administered, or length of stay. Initial and maximum doses of warfarin per kg were significantly lower in obese patients compared with nonobese patients (P<0.05). Median time to therapeutic INR value was twice as long in obese patients as in nonobese patients (median=6 [range, 4 to 28 d] versus median=3 [range, 1 to 10 d]; P<0.01). CONCLUSIONS: Obese pediatric patients have an increased time to therapeutic INR value when traditional warfarin dosing guidelines are used.

Age-based difference in activation markers of coagulation and fibrinolysis in extracorporeal membrane oxygenation.

OBJECTIVE: Coagulation system activation in extracorporeal membrane oxygenation results in hemostatic derangements. Thrombin generation markers like prothrombin fragment 1+2 and thrombin-antithrombin complex are sensitive markers of hypercoagulability. Plasmin-antiplasmin complex is a sensitive marker for fibrinolysis. D-dimers reflect thrombin generation and fibrinolysis. The aim was to identify the extent of hemostasis activation during extracorporeal membrane oxygenation by measuring thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer. DESIGN: Prospective cohort study. SETTING: Tertiary care academic center. PATIENTS: Children placed on extracorporeal membrane oxygenation from April 2011 to January 2013. INTERVENTIONS: Prothrombin fragment 1+2, thrombin-antithrombin complex, plasmin-antiplasmin complex, and D-dimer were measured on days 1 and 5 of extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Data presented as median (interquartile range); nonparametric tests were done using SPSS. Twenty-nine children (52% < 30 d old [neonates], median extracorporeal membrane oxygenation length 151 hr) were studied. Complications included thrombosis in 14%, bleeding in 45%, and thrombosis and bleeding together in 10%. Thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer levels were high on day 1 and remained increased on extracorporeal membrane oxygenation. In neonates, all levels were higher on day 5 compared with day 1: thrombin-antithrombin complex (55.6 µg/L [30.7-76.0] vs 18.7 µg/L [10.9-34.6]; p = 0.03), prothrombin fragment 1+2 (2,038 pmol/L [1,093-4,018.5] vs 377.5 pmol/L [334.3-1,103.0]; p = 0.00), plasmin-antiplasmin complex (2,160 µg/L [786-3,090] vs 398 µg/L [296.8-990.8]; p = 0.00), and D-dimer (3.0 µg/mL [1.9-11.5] vs 1.5 µg/mL [0.6-2.9]; p = 0.01). Thrombin-antithrombin complex, prothrombin fragment 1+2, plasmin-antiplasmin complex, and D-dimer levels did not correlate with anti-Xa activity or heparin dose. In bleeders older than 30 days, plasmin-antiplasmin complex stayed elevated on day 5, but in patients with no bleeding complications, plasmin-antiplasmin level showed a declining trend. In neonates, plasmin-antiplasmin levels increased over the course of extracorporeal membrane oxygenation irrespective of bleeding. CONCLUSION: Despite our best efforts at adequate anticoagulation with unfractionated heparin, neonates showed persistent increase in coagulation activation on extracorporeal membrane oxygenation. Fibrinolysis activation may contribute to bleeding in patients older than 30 days. Different anticoagulation protocols should be individualized based on age.

Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. METHODS AND RESULTS: The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. CONCLUSIONS: Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Comparison of anti-Xa levels in obese and non-obese pediatric patients receiving treatment doses of enoxaparin.

OBJECTIVE: To determine if using actual body weight to dose enoxaparin in obese pediatric patients results in higher anti-Xa levels compared with non-obese pediatric patients. STUDY DESIGN: This was a retrospective case-matched study of obese and non-obese pediatric patients receiving treatment doses of enoxaparin in a tertiary care children's hospital. Patients were included if they were initiated on treatment doses of enoxaparin, had appropriate anti-Xa levels drawn, and were between 2 and 18 years of age. Patients with renal insufficiency, hyperbilirubinemia, goal anti-Xa level <0.5 or >1 unit/mL, or receiving mechanical circulatory support were excluded. Obese patients who met study criteria were matched on a 1:1 basis with non-obese patients. RESULTS: All baseline characteristics were similar except for body mass index percentile (98.2 ± 2 vs 48.7 ± 15, P < .01). Obese patients had higher initial anti-Xa levels (0.67 ± 0.27 vs 0.53 ± 0.24 unit/mL, P = .028). Over time, obese patients required a lower mean dose to achieve therapeutic anti-Xa levels than non-obese patients (0.81 ± 0.19 vs 1.1 ± 0.4 mg/kg, P = .005). CONCLUSIONS: The mean initial anti-Xa level was higher in obese pediatric patients compared with non-obese pediatric patients, but a dosage adjustment was not required. Obese patients may need closer monitoring over time to avoid supratherapeutic levels and possible bleeding events.

A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.

Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 10(9)/L and 250 × 10(9)/L. A platelet count ≥ 50 × 10(9)/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 10(9)/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 µg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http://www.clinicaltrials.gov as NCT00515203.

Readmissions for warfarin-related bleeding in pediatric patients after hospital discharge.

BACKGROUND: Warfarin therapy in pediatric patients can be difficult to manage with bleeding as a primary adverse event. Therapy initiation can be difficult as doses to achieve therapeutic outcomes are being determined. Evaluation of readmission for bleeding in pediatric patients discharged on warfarin therapy may be useful to prevent adverse events. METHODS: The Pediatric Health Information System (PHIS) was queried to identify all patients <19 years of age who were discharged from a pediatric hospital on warfarin therapy. Patients who were readmitted with bleeding in the first 30 days after discharge were identified and patient variables, hospital stay variables, and medications at discharge were identified. Univariate and multivariate analysis was performed to identify independent risk factors for bleeding readmission. RESULTS: A total of 4,883 patients met study criteria (56% male, mean age 10.1 + 5.9 years). The two most common indications for warfarin therapy were cardiac valve replacement (23.6%) and Fontan procedure (19.5%). Ninety-seven patients (1.99%) were readmitted with bleeding within 30 days of discharge [median time 9 days (IQR 5-16 days)]. Multivariate analysis identified Asian race (OR 4.0, P < 0.01); mitral valve replacement (OR 2.5, P < 0.01); escitalopram at discharge (OR 4.2, P = 0.02); levofloxacin at discharge (OR 8.3, P < 0.01); lansoprazole at discharge (OR 1.7, P = 0.047); and length of stay (OR 1.01, P = 0.047) as significant for bleeding readmission. CONCLUSION: Pediatric patients discharged on warfarin may be readmitted for bleeding within 30 days if risk factors are present. Risk factors include patient genetic profile, drug interactions, and indications with higher goal INR values.

Risk factors for elevated INR values during warfarin therapy in hospitalized pediatric patients.

BACKGROUND: There are currently no data describing the incidence of or risk factors for elevated International Normalized Ratio (INR) values in patients receiving warfarin at a tertiary care pediatric hospital. By minimizing risk factors for elevated INR values patient morbidity may be minimized. PROCEDURES: A 6-year retrospective chart review of inpatient admissions at our institution that received warfarin was performed. Factors for elevated INR values, such as patient demographics, disease state, and medication interactions were reviewed. Patients with an INR value ≥ 0.5 above the upper limit of the goal range were compared to patients without an elevated INR value. A logistic regression analysis was performed to identify independent variables for elevated INR values. RESULTS: A total of 298 patient admissions (184 patients) met study criteria, and the largest patient population was between 1 and 12 years old (36.9%). The most common indication for warfarin was mitral valve replacement (25.5%). An elevated INR occurred in 20.8% of admissions. Logistic regression analysis identified Asian race, an elevated baseline INR value, warfarin initiation after cardiac surgery, days of inpatient warfarin therapy, and drug interactions with ciprofloxacin and lansoprazole as independent variables for an elevated INR value (P < 0.05). Obesity was significant as an independent variable for a non-elevated INR value (P < 0.05). CONCLUSIONS: Elevated INR values occur often in patients receiving warfarin while admitted to a tertiary care pediatric facility and modifiable risk factors exist for elevated INR values.

Pilot study of the effect of romiplostim on child health-related quality of life (HRQoL) and parental burden in immune thrombocytopenia (ITP).

BACKGROUND: Childhood ITP can have a negative impact on the child and his/her family even though it is typically a benign disorder with low risk of serious bleeding. In adults and now children, romiplostim increases the platelet count without significant adverse effects. In this study, the impact of romiplostim treatment on the HRQoL of children with chronic ITP was assessed using the Kid's ITP Tools (KIT). PROCEDURE: Subjects 1-18 years old, with chronic ITP (>6 months), were enrolled in a multi-center, randomized, double-blind, placebo-controlled phase 1/2 treatment study with romiplostim (reported elsewhere). Subjects and/or proxies completed the KIT at baseline, week 5, and week 13. Scores were computed for child self-report (children >7 years), proxy-report, and parent impact. Changes in mean scores from baseline to week 13 were computed. RESULTS: Twenty-two children (17 receiving romiplostim, 5 placebo) and/or their parents provided data. Change in mean scores demonstrated significant improvement in HRQoL for romiplostim versus placebo for parent impact (24 ± 17 vs. -6 ± 8; P = 0.008). Change scores for child self-report trended toward improvement with romiplostim and decreased with placebo (5 ± 10 vs. -7 ± 17; P = 0.29). Romiplostim proxy-report mean change scores were 6 points higher than placebo (8 ± 16 vs. 2 ± 12; P = 0.50). CONCLUSIONS: Romiplostim significantly reduced parental burden in this study. Whether the same and/or additional improvements in HRQoL would be demonstrated by a larger, longer study of romiplostim-treated children with ITP remains to be determined. Pediatr Blood Cancer 2012; 58: 395-398. © 2011 Wiley Periodicals, Inc.

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia.

In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

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.

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

BACKGROUND: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules. OBJECTIVES: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. PATIENTS/METHODS: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

BACKGROUND: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism. METHODS: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to <18 years, 2 to <12 years, and birth to <2 years) via interactive response technology. The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent venous thromboembolism and venous thromboembolism-related death. A non-inferiority margin of absolute differences of 20% was used. Secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]), and pharmacokinetic-pharmacodynamic relationships (descriptive analyses). This trial is registered with ClinicalTrials.gov, NCT01895777 and is completed. FINDINGS: 328 children were enrolled between Feb 18, 2014, and Nov 14, 2019. 267 were randomly assigned (90 [34%] to standard of care and 177 [66%] to dabigatran) and included in the analyses. Median exposure to standard of care was 85·0 days (IQR 80·0-90·0) and to dabigatran was 84·5 days (78·0-89·0). Similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs 81 [46%] of 177; Mantel-Haenszel weighted difference, -0·04; 90% CI -0·14 to 0·07; p<0·0001 for non-inferiority). On-treatment bleeding events were reported in 22 (24%) of 90 children receiving standard of care and 38 (22%) of 176 children receiving dabigatran (hazard ratio [HR] 1·15, 95% CI 0·68 to 1·94; p=0·61); major bleeding events were similar between the groups (two [2%] of 90 and four [2%] of 176; HR 0·94, 95% CI 0·17 to 5·16; p=0·95). Pharmacokinetic-pharmacodynamic curves showed a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time, and a non-linear relationship with activated partial thromboplastin time; curves were similar to those for adults. Serious adverse events were reported for 18 (20%) of 90 children receiving standard of care and 22 (13%) of 176 children receiving dabigatran. The most common severe adverse events were vascular disorders (standard of care three [3%] of 90, dabigatran two [1%] of 176), and gastrointestinal disorders (standard of care two [2%] of 90 and dabigatran five [3%] of 176). One on-treatment death occurred in the standard of care group (retroperitoneal bleeding, not considered treatment related by the study investigators). INTERPRETATION: An age-adjusted and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to less than 18 years with venous thromboembolism. Dabigatran was non-inferior to standard of care in terms of efficacy, with similar pharmacokinetic-pharmacodynamic relationships as those seen in adults, and might be a suitable alternative to standard of care. FUNDING: Boehringer Ingelheim.

The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children's Oncology Group.

BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. OBJECTIVE: The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. METHODS: A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. RESULTS: Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. CONCLUSION: Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.

Folate pathway genetic polymorphisms are related to attention disorders in childhood leukemia survivors.

OBJECTIVE: To test the hypothesis that 5,10-methylenetetrahydroreductase (MTHFR) polymorphisms can partially explain the individual variation in developing attention-deficit/hyperactivity disorder (ADHD) after acute lymphoblastic leukemia (ALL) therapy. STUDY DESIGN: Parents of 48 survivors of childhood ALL completed a clinical diagnostic process to identify subtypes of ADHD. Genotyping was performed with peripheral blood DNA for MTHFR (C677T and A1298C) polymorphisms. RESULTS: Eleven of the 48 patients (22.9%) had scores consistent with the inattentive symptoms of ADHD. Patients with genotypes related to lower folate levels (11 out of 39; 39.2%) were more likely to have ADHD. The A1298C genotype appeared to be the predominant linkage to the inattentive symptoms, leading to a 7.4-fold increase in diagnosis, compared with a 1.3-fold increase for the C677T genotype. Age at diagnosis and sex were not associated with inattentiveness. CONCLUSIONS: Preliminary data imply a strong relationship between MTHFR polymorphisms and the inattentive symptoms of ADHD in survivors of childhood ALL.

Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.

PURPOSE: A phase I study of intrathecal (IT) gemcitabine was performed to define a safe dose and characterize the toxicity profile and CSF pharmacokinetics of gemcitabine and its major metabolite 2',2'-difluoro-deoxyuridine (dFdU) in patients 3 years of age and older with neoplastic meningitis. EXPERIMENTAL DESIGN: Gemcitabine was administered via Ommaya reservoir or lumbar puncture at three dose levels: 5 mg weekly, 5 mg twice-weekly, and 10 mg twice-weekly using a standard phase I dose escalation design. Serial CSF samples were obtained for pharmacokinetic studies in seven patients with Ommaya reservoirs. Serial blood samples for pharmacokinetic studies were also obtained from three patients. RESULTS: Ten patients were enrolled in this study. Significant neurological toxicities occurred in two patients including myelitis in a patient at the 5 mg twice-weekly dose level and somnolence in a patient at the 10 mg twice-weekly dose level. No complete responses were seen; however, three patients had stable disease. Gemcitabine was rapidly eliminated from the CSF with a terminal half-life of 61 +/- 50 min. No gemcitabine or dFdU was detected in plasma. CONCLUSIONS: IT gemcitabine was associated with significant neurotoxicity; therefore, its further development for IT use is not recommended.

Valacyclovir and acyclovir pharmacokinetics in immunocompromised children.

BACKGROUND: Valacyclovir, an orally administered pro-drug of acyclovir, is utilized in the therapy of herpes simplex and herpes zoster infections. Little data regarding the pharmacokinetics, safety and tolerability are available for pediatric patients. This report describes acyclovir pharmacokinetics following valacyclovir administration in immunocompromised pediatric patients, compares pharmacokinetic parameters following oral valacyclovir and IV acyclovir, and provides a limited assessment of efficacy in the setting of active herpes zoster infection. PROCEDURE: A total of 37 immunocompromised children were enrolled on one of two studies. Pharmacokinetic data are available for 32 patients following valacyclovir (15 mg/kg) administration, 11 of whom also had pharmacokinetic sampling following IV acyclovir administration. Three patients received valacyclovir as treatment for herpes zoster infections. RESULTS: Mean (+/-SD) C(max) values for acyclovir following oral valacyclovir were 18.8 +/- 7 microM with a total exposure of 4,106 +/- 1,519 microM min. The mean bioavailability of acyclovir from valacyclovir was 64%. Grade 1 nausea and emesis, which occurred in five patients was the only valacyclovir-related toxicity. Two of the three patients treated for herpes zoster had complete scabbing of lesions by day 9. CONCLUSION: Valacyclovir (15 mg/kg) was well tolerated in pediatric patients and demonstrated excellent bioavailability. Consideration should be given to the use of oral valacyclovir for the treatment of herpes zoster in clinically stable pediatric oncology patients.

A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study.

PURPOSE: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia. EXPERIMENTAL DESIGN: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle. RESULTS: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses. CONCLUSIONS: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.