Tamara van Donge

Ibuprofen-related maturational adverse events in ELBW neonates 155 8 kidney function. The current study aims to quantify the impact of ibuprofen treatment on serum creatinine concentrations, at various periods during early and late neonatal life, addressing the potential adverse drug reactions of ibuprofen, affected by the postnatal maturation. To illustrate the effect of ibuprofen treatment on serum creatinine profiles in cases with different gestational and postnatal ages, we simulated serum creatinine profiles during ibuprofen exposure for four typical neonates with varying gestational ages of 24, 27, 29 and 32 weeks, respectively. The ibuprofen treatment comprised three different treatment periods of three constituent days: either day 1 to 3 (first week of life), or day 15 to day 17 (third week of life) or day 29 to day 32 (fifth week of life) after birth. In the current dataset, ibuprofen was administered according to the current label, i.e. 10, 5, 5 mg/kg respectively at 24-hour intervals. Simulations were performed using the mlxR package in R (version 3.5.1; R Development Core Team, Vienna, Austria, http://r-project.org) , with the inclusion of the population parameters derived of the dynamic model which was developed in Monolix (version 2019R1. Antony, France: Lixoft SAS, 2020, http://lixoft.com/products/monolix/ ). We compared the predicted serum creatinine concentration and creatinine clearance over a period of six weeks after birth for typical ELBW cases who were exposed to ibuprofen or not. Results Serum creatinine dynamic model Predicted serum creatinine concentration profiles for four typical ELBW neonates are shown in Figure 1. Generally, an increase in serum creatinine concentrations is observed during treatment with ibuprofen, with a more pronounced effect during the early neonatal life, i.e. the first week of life. The difference in the serum creatinine concentrations between patients receiving ibuprofen and patients not exposed decreases with postnatal age; this trend is independent of gestational age (Table 1). Table 2 illustrates the serum creatinine concentrations for the four different gestational ages, separated by the presence or absence of ibuprofen treatment for the three different postnatal periods (week 1, 3 or 5 after birth). The extent of the increase of serum creatinine concentrations due to ibuprofen treatment is the most pronounced during the first week of life (i.e. round 1). For instance, for a neonate born at 24 weeks gestation, the creatinine concentrations increase from 0.383 mg/dL to 0.906 or 0.876 in the presence or absence of ibuprofen treatment, respectively (Table 2). This elevation of creatinine concentrations is less pronounced later in life, as the difference in creatinine concentrations between ibuprofen treatment and baseline is practically negligible for week 3 and 5 after birth (Table 1).