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

Purpose: Ibuprofen 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. Methods: We 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. Results: The 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. Conclusions: We 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.