Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".