TY - JOUR
T1 - Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy
AU - Roberts, Jessica K.
AU - Stockmann, Chris
AU - Ward, Robert M.
AU - Beachy, Joanna C.
AU - Baserga, Mariana C.
AU - Spigarelli, Michael G.
AU - Sherwin, Catherine M.T.
N1 - This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s40262-015-0286-y
PY - 2015/5/20
Y1 - 2015/5/20
N2 - 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.
AB - 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.
KW - Erythropoietin
KW - Therapeutic Hypothermia
KW - Darbepoetin Alfa
KW - Objective Function Value
KW - Normalize Prediction Distribution Error
UR - https://corescholar.libraries.wright.edu/pediatrics/252
U2 - 10.1007/s40262-015-0286-y
DO - 10.1007/s40262-015-0286-y
M3 - Article
C2 - 25989868
VL - 54
SP - 1237
EP - 1244
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
ER -