BackgroundAminoglycosides are administered to treat (suspected) neonatal sepsis. The pharmacokinetics (PK) of this antibiotic class are expected to be different in neonates with perinatal asphyxia (PA) treated with therapeutic hypothermia (TH). Effective exposure of the aminoglycoside amikacin in neonates is achieved using a prospectively validated population PK mod-el-derived dosing regimen.1 However, dosing adjust-ments in case of PA with TH are lacking. The aim of the current (AMICOOL) study was to further explore amikacin disposition in neonates by quantifying the impact of PA treated with TH on amikacin clearance and to provide dosing recommendations for this specific patient population.MethodsAmikacin therapeutic drug monitoring data were retrospectively collected from term neonates with PA treated with TH and admitted to the neonatal inten-sive care units of VUmc Amsterdam and the University Hospitals Leuven between 2010–2015. Data were added to the original published amikacin population PK dataset.2 A data-driven covariate analysis was performed to assess the impact of PA treated with TH on amikacin clearance. Monte Carlo simulations facilitated the comparison of simulated amikacin exposures using the current dosing guidelines.1 and proposed dosing adaptations for PA treated with TH. We hereby aimed to achieve optimal amikacin trough (<5 mg/L) and peak (>24 mg/L) levels. Stochastic simulations were used to investigate the differ-ences in exposure among typical neonates with PA and TH with varying birth weights (1965–4220 g).ResultsData of 55 neonates with PA treated with TH were added to the original amikacin population PK dataset of 930 neonates.2 A 40.6% (RSE 9%) decrease in amikacin clearance for neonates with PA with TH was documented. Based on Monte Carlo simulations, the current dosing guidelines resulted in 40%–57% of neonates with PA and TH displaying amikacin trough concentrations above the toxic trough level (>5 mg/L), while an additional increase of the dosing interval with 12 hours decreased this percentage to 14%. Stochastic simulations showed that among typical neonates the percentage of patients with trough concentrations>5 mg/L ranges 14% to 25%.ConclusionIn neonates with perinatal asphyxia treated with therapeutic hypothermia, amikacin clearance is reduced with 40.6%. Based on simulations, an additional prolongation of the dosing interval with 12 hours results in optimised amikacin exposure and reduces toxicity in this specific population. As a future perspective, the model-based dosing proposal needs prospective validation. Since amikacin can be used as a surrogate for glomerular filtration, clearance of other drugs using the same elimination route could also be reduced in case of perinatal asphyxia treated with therapeutic hypothermia and may require further dosing adaptations.

BackgroundKetorolac, a potent non-steroidal anti-in-flammatory drug, is a chiral substance. Racemic ketorolac clearance is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. We aimed to document the impact of pregnancy and postpartum on enantiomer-specific (S and R) ketorolac pharmacokinetics (PK) in young women.MethodsObservations shortly following caesarean de-livery (n=39) were pooled with data in subgroup of these women (n=8/39) four months afterwards (‘postpartum’) and with 8 healthy female volunteers, resulting in 47 un-paired and 8 paired PK estimates. All women received single intravenous bolus of ketorolac tromethamine (30 mg). Five (at 1, 2, 4, 6, 8 hour) plasma samples were collected and plasma concentrations were determined using HPLC method. Enantiomer-specific PKs were calculated using PKSolver.ResultsUnpaired analysis documented that median distribution volume at steady state (Vss) for S-and R-ke-torolac was significantly higher in women following cae-sarean delivery (n=31) compared to postpartum (n=8) (S-ketorolac: 12.79 vs. 7.84 L, p=0.011; R-ketorolac: 8.96 vs. 5.86 L, p=0.001) or to healthy female volunteers (n=8).(S-ketorolac: 12.79 vs. 9.14 L, p=0.002; R-ketorolac: 8.96 vs. 5.51 L, p<0.001). When corrected for BW, median Vss for both S-and R-ketorolac were significantly higher in women shortly following caesarean delivery compared to those in healthy female volunteers (S-ketorolac: 0.18 vs. 0.15 L/kg, p=0.037; R-ketorolac: 0.12 vs. 0.09 L/kg, p=0.001). The median clearance (CL) for S-and R-ketoro-lac was significantly higher in women following caesarean delivery compared to postpartum (S-ketorolac: 6.49 vs. 3.73 L/h, p<0.001; R-ketorolac: 2.14 vs. 1.43 L/h, p=0.002) or to healthy female volunteers (S-ketorolac: 6.49 vs. 3.60 L/h, p<0.001; R-ketorolac: 2.14 vs. 0.99 L/h, p=0.001). After taking the body size differences into account, CL to body weight (CL/BW) and CL to body surface area (CL/BSA) for S-and R-ketorolac were also higher following caesar-ean delivery compared to observations in postpartum (S-ketorolac:+33.3%, L/h·kg,+38.6%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+31.4%, L/h·m2) and in healthy female volunteers (S-ketorolac:+33.3%, L/h·kg,+48.4%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+56.8%, L/h·m2). In addition, S/R-ketorolac CL/BSA ratio was significantly higher at de-livery compared to postpartum (3.07 vs. 2.73, p=0.020). Paired PK analysis in 8 women following delivery or post-partum showed the same pattern. Finally, the simultane-ous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis.ConclusionPregnancy affects S-, R-and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ke-torolac CL and S/R-ketorolac CL ratio is higher following delivery compared to postpartum or to healthy female volunteers. For definitive physiological state-specific dos-ing recommendations in women, we encourage future repeated dos...