Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns

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 20mgkg(-1) followed by 10mgkg(-1) every 24h. Simulations of this dosing regimen show an (S)-ibuprofen trough concentration of 43mgL(-1) is reached at 48h, which we assumed the target through concentration. We show that this target can be reached with a first dose of 18mgkg(-1), followed by 4mgkg(-1) every 12h. After 96h postnatal age, the dose should be increased to 5mgkg(-1) every 12h 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.