Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus

Aims: Racemic ibuprofen is widely used for the treatment of preterm neonates with patent ductus arteriosus. Currently used bodyweight-based dosing guidelines are based on total ibuprofen, while only the S-enantiomer of ibuprofen is pharmacologically active. We aimed to optimize ibuprofen dosing for preterm neonates of different ages based on an enantiomer-specific population pharmacokinetic model. Methods: We prospectively collected 210 plasma samples of 67 preterm neonates treated with ibuprofen for patent ductus arteriosus (median gestational age [GA] 26 [range 24–30] weeks, median body weight 0.83 [0.45–1.59] kg, median postnatal age [PNA] 3 [1–12] days), and developed a population pharmacokinetic model for S- and R-ibuprofen. Results: We found that S-ibuprofen clearance (CL _S, 3.98 mL/h [relative standard error {RSE} 8%]) increases with PNA and GA, with exponents of 2.25 (RSE 6%) and 5.81 (RSE 15%), respectively. Additionally, a 3.11-fold higher CL _S was estimated for preterm neonates born small for GA (RSE 34%). Clearance of R-ibuprofen was found to be high compared to CL _S (18 mL/h [RSE 24%]), resulting in a low contribution of R-ibuprofen to total ibuprofen exposure. Current body weight was identified as covariate on both volume of distribution of S-ibuprofen and R-ibuprofen. Conclusion: S-ibuprofen clearance shows important maturation, especially with PNA, resulting in an up to 3-fold increase in CL _S during a 3-day treatment regimen. This rapid increase in clearance needs to be incorporated in dosing guidelines by adjusting the dose for every day after birth to achieve equal ibuprofen exposure.