Precision Dosing of Oral Ibuprofen for PDA, A Pilot RCT

Summary

Newborns born early are at risk for a serious health problem called patent ductus arteriosus (PDA). PDA is a passageway between heart and lung that can cause life-threatening complications such as bleeding in the brain or even death if it remains open and large. When closure of PDA is needed, doctors make every attempt to do it as soon as possible. Ibuprofen is the best drug to close the PDA, but it only works for 50% of small newborns. The investigators have shown before that small newborns handle ibuprofen differently and the amount of active ibuprofen that reaches their blood can be very unpredictable. Studies have shown if enough ibuprofen reaches the body, it can close the PDA. Therefore the investigators designed this study to see whether it is possible to give each newborn the right amount of ibuprofen that their body needs to close the PDA. The investigators will compare two ways to give ibuprofen in a small number of newborns: 1 - standard amount of ibuprofen to everyone, which is the usual care or 2 - ibuprofen doses that will be changed based on how much active ibuprofen has reached the body and how well the newborn's PDA is closing. The investigators will then compare the number of PDAs closed in each group and closely monitor any possible challenges for this new practice. By doing this project, the goals can be summarized as below: A. Primary goal: To determine if it is feasible to successfully run a larger study in the future. B. Secondary goals 1. To assess how well and how safely the personalized (MIPD) method works, using a tool called WAPPS-PDA to guide dosing. 2. To compare the effectiveness and safety of the personalized method with standard ibuprofen dosing. 3. To identify drug levels in the blood (Cmin, AUC0-24, AUC0-72) that are associated with complete, partial, or no response to treatment.

Timeline

Start

2024-07-04

Primary completion

2026-07

Completion

2027-07

Publications

• Background McEneny-King A, Foster G, Iorio A, Edginton AN. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo). JMIR Res Protoc. 2016 Dec 7;5(4):e232. doi: 10.2196/resprot.6559.
• Background Euteneuer JC, Kamatkar S, Fukuda T, Vinks AA, Akinbi HT. Suggestions for Model-Informed Precision Dosing to Optimize Neonatal Drug Therapy. J Clin Pharmacol. 2019 Feb;59(2):168-176. doi: 10.1002/jcph.1315. Epub 2018 Sep 11.
• Background Van Overmeire B, Touw D, Schepens PJ, Kearns GL, van den Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001 Oct;70(4):336-43.
• Background Hirt D, Van Overmeire B, Treluyer JM, Langhendries JP, Marguglio A, Eisinger MJ, Schepens P, Urien S. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol. 2008 May;65(5):629-36. doi: 10.1111/j.1365-2125.2008.03118.x. Epub 2008 Feb 27.
• Background Engbers AGJ, Voller S, Flint RB, Goulooze SC, de Klerk J, Krekels EHJ, van Dijk M, Willemsen SP, Reiss IKM, Knibbe CAJ, Simons SHP. The Effect of Ibuprofen Exposure and Patient Characteristics on the Closure of the Patent Ductus Arteriosus in Preterm Infants. Clin Pharmacol Ther. 2022 Aug;112(2):307-315. doi: 10.1002/cpt.2616. Epub 2022 May 6.
• Background Barzilay B, Youngster I, Batash D, Keidar R, Baram S, Goldman M, Berkovitch M, Heyman E. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2012 Mar;97(2):F116-9. doi: 10.1136/adc.2011.215160. Epub 2011 Aug 11.
• Background Samiee-Zafarghandy S, van Donge T, Fusch G, Pfister M, Jacob G, Atkinson A, Rieder MJ, Smit C, Van Den Anker J. Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates. Arch Dis Child. 2022 Jan;107(1):86-91. doi: 10.1136/archdischild-2020-321381. Epub 2021 May 11.
• Background Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, Zea AM, Zhang Y, Sadeghirad B, Thabane L. Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA. 2018 Mar 27;319(12):1221-1238. doi: 10.1001/jama.2018.1896.

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