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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (<i>n</i> = 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. <b><i>Results:</i></b> 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 AUC<sub>72h</sub> 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. <b><i>Discussion:</i></b> 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.

The impact of the route of administration on the efficacy and safety of the drug therapy for patent ductus arteriosus in premature infants: a systematic review and meta-analysis

“…Given that ibuprofen was a racemic mixture of inactive R and active S mirror-image enantiomers, this suggests that oral ibuprofen administration contributes to a higher concentration of active ibuprofen compared to intravenous administration. However, the study conducted by Smit et al (2023) contradicts this notion showing that the concentration of S-ibuprofen associated with oral ibuprofen was lower than that with intravenous administration for a significant portion of the dosing interval in preterm infants with hsPDA. This indicates that delayed absorption following oral ibuprofen administration may not lead to increased S-ibuprofen concentration ( Smit et al, 2023 ).…”

“…However, the study conducted by Smit et al (2023) contradicts this notion showing that the concentration of S-ibuprofen associated with oral ibuprofen was lower than that with intravenous administration for a significant portion of the dosing interval in preterm infants with hsPDA. This indicates that delayed absorption following oral ibuprofen administration may not lead to increased S-ibuprofen concentration ( Smit et al, 2023 ). Also noted that the higher peak concentration of ibuprofen after intravenous administration might lead to decreased glomerular filtration rates, increased fluid load, and reduced PDA closure rates.…”

Comparative effectiveness of the medication versus non-medication approach for closing symptomatic patent ductus arteriosus in Extreme low birth weight infant; Based on national wide cohort study

“…Given the delayed absorption by OG, IV was the preferred route for immediate PDA closure. Recent meta-analyses have indicated that the e cacy of OG administration is superior to that of IV administration, potentially due to the harmful effects of high peak concentrations observed with IV administration (18,48,49). Consequently, it was anticipated that the IV group would experience higher complications and mortalities compared to the OG group.…”