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

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.

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.

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.

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.