Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

ABSTRACT: The primary objective of this work was to determine the optimal time for administration of an erythropoietin (Epo) dose to maximize the erythropoietic effect using a simulation study based on a young sheep pharmacodynamic model. The dosing optimization was accomplished by extending a Hb production pharmacodynamic model, which evaluates the complex dynamic changes in the Epo recepto

Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants

Background: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia. Methods: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity. Results: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively. Conclusions: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity

Pharmacokinetic Analysis of Continuous Erythropoietin Receptor Activator Disposition in Adult Sheep Using a Target-Mediated, Physiologic Recirculation Model and a Tracer Interaction Methodology

The pharmacokinetics (PK) of continuous erythropoietin receptor activator (CERA), a PEGylated erythropoietin (EPO) derivative, was studied in sheep after bone marrow (BM) busulfan ablation by using a receptor-based recirculation model and tracer interaction method (TIM) experiments. The nontracer CERA component of the TIM was analyzed using a noncompartmental approach. In contrast to EPO elimination that is linear after the BM ablation, CERA elimination remains nonlinear. After busulfan treatment, initial EPO receptors (EPOR) normalized production rate constant, EPOR degradation rate constant, and CERA-EPOR complex internalization rate constant decreased (p < 0.01), whereas no change in CERA/EPOR equilibrium dissociation constant was detected (p > 0.05). After BM ablation, noncompartmental analysis showed that CERA-PK parameters underwent 1) a decrease in plasma clearance (p < 0.01); 2) a concomitant increase in elimination half-life and mean residence time; and 3) no significant change in volume of distribution, distribution half-life, or distributional clearance (p > 0.05). These results suggest that CERA elimination is mediated through saturable hematopoietic and nonhematopoietic EPOR pathways, with possible contribution of another EPOR-independent pathway(s). Compared with the nonhematopoietic EPOR population, the hematopoietic receptors have similar affinity to CERA but are significantly more involved in CERA's in vivo elimination. The saturable nature of the nonerythropoietic, non-BM pathway(s) for CERA in contrast to EPO predicts two fundamental differences: 1) an increasing fraction of CERA is used for erythropoiesis for increasing concentrations; and 2) the clearance of CERA becomes more limited for increasing concentrations. Taken together, these differences favor a more efficacious and prolonged action for CERA

Receptor-Based Dosing Optimization of Erythropoietin in Juvenile Sheep after Phlebotomy

The primary objective of this work was to determine the optimal time for administration of an erythropoietin (Epo) dose to maximize the erythropoietic effect using a simulation study based on a young sheep pharmacodynamic model. The dosing optimization was accomplished by extending a Hb production pharmacodynamic model, which evaluates the complex dynamic changes in the Epo receptor (EpoR) pool from the changes in Epo clearance. Fourteen healthy 2-month-old sheep were phlebotomized to Hb levels of 3 to 4 g/dl. Epo clearance was evaluated longitudinally in each animal by administering tracer doses of 125I-recombinant human Epo multiple times during the experiment. Kinetic parameters were estimated by simultaneously fitting to Hb data and Epo clearance data. The phlebotomy caused a rapid temporary increase in the endogenous Epo plasma level. The Hb began to increase after the increased in the Epo level with a lag time of 1.13 ± 0.79 days. The average correlation coefficients for the fit of the model to the Hb and clearance data were 0.953 ± 0.018 and 0.876 ± 0.077, respectively. A simulation study was done in each sheep with fixed individual estimated model parameters to determine the optimal time to administer a 100 U/kg intravenous bolus Epo dose. The optimal dose administration time was 11.4 ± 6.2 days after phlebotomy. This study suggests that the Hb produced from Epo administration can be optimized by considering the dynamic changes in the EpoR pool

Cost Analysis of Neonatal In-Line Ex Vivo Point-of-Care Monitoring

A hypothetical model using a base case and sensitivity analyses compared averted and incurred costs of in-line monitoring with neonatal intensive care unit satellite laboratory testing. Data were obtained retrospectively for 1 year from 50 consecutive critically ill premature neonates weighing less than 1,000 g at birth whose blood tests were performed in-line and processed at the satellite laboratory. Averted costs included phlebotomies, satellite blood testing, and transfusions; incurred costs included in-line monitor rental, nursing time, and daily monitor validation. In-line monitoring led to cost savings of $324 per neonate and a benefit/cost ratio (BCR) of 1.23 in our base case. Sensitivity and scenario analyses addressed uncertainty and led to a BCR variation of 0.41 to 2.48. Compared with satellite laboratory testing, in-line monitoring of critically ill neonates may generate cost savings through reduced laboratory analysis expense, less phlebotomy loss, and fewer blood transfusions for hospitals with high laboratory cost structures. Because most cost savings result from offsetting indirect costs (eg, building space and hospital overhead) that are of a longer term nature, short-run cost savings are less likely to be realized

Cost-effectiveness of a limited-donorblood program for neonatal red cell transfusions

BACKGROUND: Very-low-birthweight infants have typically been given fresh red cells (RBCs), a practice in which aliquots of RBCs for several infants were issued each day from a single unit. Recently, to limit donor exposures, large volumes of RBCs are reserved for the long-term transfusion support of individual infants. STUDY DESIGN AND METHODS: Medical records were examined retrospectively to assess the costs of a limited-donor program for providing RBC transfusions to very-low-birthweight infants. Costs of multiple- and limited-donor programs were compared by using two samples of 30 consecutive infants treated at The University of Iowa Hospitals and Clinics in 1993 and 1997. Effectiveness was evaluated with respect to the number of donor exposures per infant. RESULTS: The cost, in 1997 dollars, of preparing each small-volume transfusion in the multiple-donor program was $27.86 per transfusion, while that in the limited-donor program was$34.83. This difference was largely attributable to use of white cell reduction in association with the limited-donor program in 1997. Eliminating the costs associated with white cell reduction rendered the costs of the limited- and multiple-donor transfusions comparable. The limited-donor program had donor exposures of 2.0 per infant, while the multiple-donor program had 3.6 exposures per infant (p\u3c0.002). CONCLUSION: The limited-donor blood program reduces donor exposure without adversely affecting costs