Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

Cornelis Smit, Aline G.J. Engbers, Samira Samiee-Zafarghandy, Tamara Van Donge, Sinno H.P. Simons, Robert B. Flint, Marc Pfister, Catherijne A.J. Knibbe*, John N. Van Den Anker

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Introduction: Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. Methods: Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (n = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. Results: Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to S-conversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25-32% increase in S-ibuprofen exposure following oral administration with AUC72h values varying between 700-2,213 mg∗h/L (oral) and 531-1,762 (IV) for the standard or 1,704-2,893 (oral) and 1,295-2,271 mg∗h/L (IV) for PNA-based dosing. Discussion: The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing.

Original languageEnglish
JournalNeonatology
DOIs
Publication statusE-pub ahead of print - 2022

Bibliographical note

Funding Information:
Study A was funded by the Netherlands Organisation for Health Research and Development (ZonMw) (Grant No. 836011022). Samira Samiee-Zafarghandy is supported by the New Investigator Fund, Hamilton Health Sciences. Cornelis Smit, Tamara van Donge, Marc Pfister, and John van den Anker are supported by the Eckenstein-Geigy foundation.

Publisher Copyright:
© 2022 The Author(s). Published by S. Karger AG, Basel.

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