Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass
Methylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)–induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)‐6 and IL‐10 concentrations from neonates enrolled in a randomized trial comparing one vs. two dose...
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Online Access: | https://doi.org/10.1002/psp4.12470 |
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doaj-e75cbcf7fd6441199009fe8672187aa12020-11-25T03:46:08ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062019-12-0181291392210.1002/psp4.12470Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary BypassChristoph P. Hornik0Daniel Gonzalez1Julie Dumond2Huali Wu3Eric M. Graham4Kevin D. Hill5Michael Cohen‐Wolkowiez6Duke Clinical Research Institute Duke University School of Medicine Durham North Carolina USADivision of Pharmacotherapy and Experimental Therapeutics University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacotherapy and Experimental Therapeutics University of North Carolina Eshelman School of Pharmacy The University of North Carolina at Chapel Hill Chapel Hill North Carolina USADuke Clinical Research Institute Duke University School of Medicine Durham North Carolina USADepartment of Pediatrics Medical University of South Carolina Charleston South Carolina USADuke Clinical Research Institute Duke University School of Medicine Durham North Carolina USADuke Clinical Research Institute Duke University School of Medicine Durham North Carolina USAMethylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)–induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)‐6 and IL‐10 concentrations from neonates enrolled in a randomized trial comparing one vs. two doses of methylprednisolone to develop indirect response population pharmacokinetic/pharmacodynamic models characterizing the exposure–response relationships. We applied the models to simulate methylprednisolone dosages resulting in the desired IL‐6 and ‐10 exposures, known mediators of CPB‐induced inflammation. A total of 64 neonates (median weight 3.2 kg, range 2.2–4.3) contributed 290 plasma methylprednisolone concentrations (range 1.07–12,700 ng/mL) and IL‐6 (0–681 pg/mL) and IL‐10 (0.1–1125 pg/mL). Methylprednisolone plasma exposure following a single 10 mg/kg intravenous dose inhibited IL‐6 and stimulated IL‐10 production when compared with placebo. Higher (30 mg/kg) or more frequent (twice) dosing did not confer additional benefit. Clinical efficacy studies are needed to evaluate the effect of optimized dosing on outcomes.https://doi.org/10.1002/psp4.12470 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christoph P. Hornik Daniel Gonzalez Julie Dumond Huali Wu Eric M. Graham Kevin D. Hill Michael Cohen‐Wolkowiez |
spellingShingle |
Christoph P. Hornik Daniel Gonzalez Julie Dumond Huali Wu Eric M. Graham Kevin D. Hill Michael Cohen‐Wolkowiez Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass CPT: Pharmacometrics & Systems Pharmacology |
author_facet |
Christoph P. Hornik Daniel Gonzalez Julie Dumond Huali Wu Eric M. Graham Kevin D. Hill Michael Cohen‐Wolkowiez |
author_sort |
Christoph P. Hornik |
title |
Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass |
title_short |
Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass |
title_full |
Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass |
title_fullStr |
Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass |
title_full_unstemmed |
Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass |
title_sort |
population pharmacokinetic/pharmacodynamic modeling of methylprednisolone in neonates undergoing cardiopulmonary bypass |
publisher |
Wiley |
series |
CPT: Pharmacometrics & Systems Pharmacology |
issn |
2163-8306 |
publishDate |
2019-12-01 |
description |
Methylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)–induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)‐6 and IL‐10 concentrations from neonates enrolled in a randomized trial comparing one vs. two doses of methylprednisolone to develop indirect response population pharmacokinetic/pharmacodynamic models characterizing the exposure–response relationships. We applied the models to simulate methylprednisolone dosages resulting in the desired IL‐6 and ‐10 exposures, known mediators of CPB‐induced inflammation. A total of 64 neonates (median weight 3.2 kg, range 2.2–4.3) contributed 290 plasma methylprednisolone concentrations (range 1.07–12,700 ng/mL) and IL‐6 (0–681 pg/mL) and IL‐10 (0.1–1125 pg/mL). Methylprednisolone plasma exposure following a single 10 mg/kg intravenous dose inhibited IL‐6 and stimulated IL‐10 production when compared with placebo. Higher (30 mg/kg) or more frequent (twice) dosing did not confer additional benefit. Clinical efficacy studies are needed to evaluate the effect of optimized dosing on outcomes. |
url |
https://doi.org/10.1002/psp4.12470 |
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