• Robert B Flint, Rob Ter Heine, Edwin Spaans, David M Burger, Johan C A de Klerk, Karel Allegaert, KnibbeCatherijne A JCAJLeiden Amsterdam Center for Drug Research (LACDR), Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands., and SimonsSinno H PSHPDepartment of Pediatrics, Division of Neonatology, Erasmus University Medical Center - Sophia Children's Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands..
• Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center - Sophia Children's Hospital, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands. r.flint@erasmusmc.nl.
• Eur. J. Clin. Pharmacol. 2018 Dec 1; 74 (12): 1585-1591.

PurposeIbuprofen is the drug of choice for treatment of patent ductus arteriosus (PDA). There is accumulating evidence that current ibuprofen-dosing regimens for PDA treatment are inadequate. We aimed to propose an improved dosing regimen, based on all current knowledge.MethodsWe performed a literature search on the clinical pharmacology and effectiveness of ibuprofen. (R)- and (S)-ibuprofen plasma concentration-time profiles of different dosing regimens were simulated using a population pharmacokinetic model and evaluated to obtain a safe, yet likely more efficacious ibuprofen exposure.ResultsThe most effective intravenous ibuprofen dosing in previous clinical trials included a first dose of 20 mg kg-1 followed by 10 mg kg-1 every 24 h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43 mg L-1 is reached at 48 h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18 mg kg-1, followed by 4 mg kg-1 every 12 h. After 96 h postnatal age, the dose should be increased to 5 mg kg-1 every 12 h due to maturation of clearance. This twice-daily dosing has the advantage over once-daily dosing that an effective trough level may be maintained, while peak concentrations are substantially (22%) lower.ConclusionsWe propose to improve intermittent ibuprofen-dosing regimens by starting with a high first dose followed by a twice-daily maintenance dosing regimen that requires increase over time and should be continued until sufficient effect has been achieved.

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