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

<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_72h 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.