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Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants

OBJECTIVES: The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for...

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Autores principales: Pfiffner, Miriam, Berger-Olah, Eva, Vonbach, Priska, Pfister, Marc, Gotta, Verena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926166/
https://www.ncbi.nlm.nih.gov/pubmed/35311056
http://dx.doi.org/10.3389/fped.2022.837492
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author Pfiffner, Miriam
Berger-Olah, Eva
Vonbach, Priska
Pfister, Marc
Gotta, Verena
author_facet Pfiffner, Miriam
Berger-Olah, Eva
Vonbach, Priska
Pfister, Marc
Gotta, Verena
author_sort Pfiffner, Miriam
collection PubMed
description OBJECTIVES: The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1–3 months old. METHODS: PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold). RESULTS: Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26–56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min. CONCLUSION: This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1–0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.
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spelling pubmed-89261662022-03-17 Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants Pfiffner, Miriam Berger-Olah, Eva Vonbach, Priska Pfister, Marc Gotta, Verena Front Pediatr Pediatrics OBJECTIVES: The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1–3 months old. METHODS: PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold). RESULTS: Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26–56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min. CONCLUSION: This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1–0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population. Frontiers Media S.A. 2022-03-02 /pmc/articles/PMC8926166/ /pubmed/35311056 http://dx.doi.org/10.3389/fped.2022.837492 Text en Copyright © 2022 Pfiffner, Berger-Olah, Vonbach, Pfister and Gotta. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Pfiffner, Miriam
Berger-Olah, Eva
Vonbach, Priska
Pfister, Marc
Gotta, Verena
Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title_full Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title_fullStr Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title_full_unstemmed Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title_short Pharmacometric Analysis of Intranasal and Intravenous Nalbuphine to Optimize Pain Management in Infants
title_sort pharmacometric analysis of intranasal and intravenous nalbuphine to optimize pain management in infants
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926166/
https://www.ncbi.nlm.nih.gov/pubmed/35311056
http://dx.doi.org/10.3389/fped.2022.837492
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