Jessica K Roberts1, Chris Stockmann1,2, Robert M Ward1,2,3, Joanna Beachy3, Mariana C Baserga3, Michael G Spigarelli1,2, Catherine M T Sherwin4. 1. Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. 2. Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. 3. Division of Neonatology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. 4. Division of Clinical Pharmacology, Department of Pediatrics, School of Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. catherine.sherwin@hsc.utah.edu.
Abstract
AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. METHODS:Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS:Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.
RCT Entities:
AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemicencephalopathy treated with hypothermia. METHODS: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemicencephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemicencephalopathy. Clearance decreased with increasing gestational age.
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