Open AccessPopulation Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass
Author(s) -
Hornik Christoph P.,
Gonzalez Daniel,
Dumond Julie,
Wu Huali,
Graham Eric M.,
Hill Kevin D.,
CohenWolkowiez Michael
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12470
Subject(s) - cardiopulmonary bypass , pharmacodynamics , medicine , pharmacokinetics , methylprednisolone , population pharmacokinetics , anesthesia , population , environmental health
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.