Evaluation of a Pediatric Enoxaparin Dosing Protocol and the Impact on Clinical Outcomes.

OBJECTIVES: Enoxaparin has been studied for prophylaxis and treatment of thromboembolism in the pediatric population. Dose-finding studies have suggested higher mean maintenance dose requirements in younger children; however, the current recommended dosing schema endorsed by the American College of Chest Physicians remains conservative, likely secondary to limited data on the safety and efficacy of escalated starting doses. Primary objectives of this study included the identification of patient characteristics and risk factors with associations to anti-factor Xa (anti-Xa) values. The secondary objective was to determine an association between the initial anti-Xa value and thrombus resolution. Safety outcomes related to bleeding were also assessed. METHODS: This retrospective cohort study reviewed records of all pediatric patients ≤18 years of age who were initiated on therapeutic subcutaneous enoxaparin between October 1, 2008, and October 1, 2018, at Children's Hospitals and Clinics of Minnesota for an indication of incident thrombus (N = 283). RESULTS: Successful resolution of thrombus was directly associated with attaining a therapeutic anti-Xa concentration upon first laboratory evaluation. Other characteristics with associations to initial anti-Xa values included age, body mass index, and certain diagnoses. The rate of composite bleeding was consistent across concentrations of anti-Xa (p = 0.4944). CONCLUSIONS: Despite adherence to protocol, the current enoxaparin dosing nomogram is only successful at achieving a therapeutic anti-Xa concentration (0.5-1.0 unit/mL) 55.8% of the time. A more aggressive enoxaparin dosing nomogram is warranted, as delaying time to therapeutic anti-Xa values impacts clinical outcomes, specifically thrombus resolution. Further investigation into characteristics with association to anti-Xa concentrations is needed.

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate®): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup.

BACKGROUND AND OBJECTIVE: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. METHODS: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. RESULTS: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. CONCLUSIONS: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Hydroxyurea use in young infants with sickle cell disease.

BACKGROUND: Hydroxyurea (HU) reduces complications and improves quality and duration of life in sickle cell disease. Evidence supports the use of HU starting after nine months of age. PROCEDURES: We performed a retrospective study of patients starting HU at less than five years of age between January 1, 2008, and December 31, 2016. We evaluated clinical events, laboratory data, and toxicity between three different age groups: cohort 1 (0-1 year), cohort 2 (1-2 years), and cohort 3 (2-5 years). RESULTS: Sixty-five patients were included in the analysis. The mean age was 7.2 months (n = 35), 19.5 months (n = 13), and 35.5 months (n = 17) for cohorts 1, 2, and 3, respectively. Cohort 1 had higher hemoglobin (P = 0.0003) and MCV (P = 0.0199) and lower absolute reticulocyte count (P = 0.0304) at 24 months of age compared with cohort 3. The absolute neutrophil count (ANC) was lower compared with both older cohorts (P = 0.0364, 0.0025). The mean baseline hemoglobin F in cohort 1 was 31.5% compared with 19.7% and 16.5% in cohorts 2 and 3, respectively (P = 0.002, P < 0.0001). The mean duration of therapy was 31.3 months, 57.6 months (P = 0.018), and 29.1 months (P = 0.401), respectively. Mean Hb F levels remained higher in cohort 1 (29.9%) compared with cohorts 2 and 3 (20.4%, P = 0.007; 20.6%, P = 0.003). Cohort 1 experienced fewer hospitalizations (P = 0.0025), pain crises (P = 0.0618), and transfusions (P = 0.0426). There was no difference in toxicity between groups. CONCLUSION: HU is safe and effective in patients 5 to 12 months of age and generated a more robust response compared with initiation in older patients.