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

• Published in: European journal of clinical pharmacology 2018-12, Vol.74 (12), p.1585-1591
• Main Authors: Flint, Robert B., ter Heine, Rob, Spaans, Edwin, Burger, David M., de Klerk, Johan C. A., Allegaert, Karel, Knibbe, Catherijne A. J., Simons, Sinno H. P.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biomedical and Life Sciences; Biomedicine; Clinical trials; Computer Simulation; Congenital diseases; Coronary vessels; Ductus Arteriosus, Patent - drug therapy; Ductus Arteriosus, Patent - metabolism; Female; Humans; Ibuprofen; Ibuprofen - administration & dosage; Ibuprofen - pharmacokinetics; Ibuprofen - therapeutic use; Infant, Newborn; Infant, Premature; Injections, Intravenous; Intravenous administration; Male; Models, Statistical; Neonates; Nonsteroidal anti-inflammatory drugs; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Stereoisomerism
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-018-2529-y

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.