Background: Lisinopril, an angiotensin-converting enzyme inhibitor (ACEi), is a frequently prescribed antihypertensive drug in the pediatric population, while being used off-label under the age of 6 years in the US and for all pediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive pediatric patients corresponding with the day-to-day clinical population. Methods: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05mg.kg-1 to 0.2 mg.kg-1. Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2kg (median 53.2kg). All data were analyzed using Monolix version 2020R1 (Lixoft®, France) and R version 3.6.2. Results: A one-compartment model with 1st order absorption and 1st order elimination optimally describes the data. Parameter estimates of ka (0.077h-1 [9.6%], typical value [relative standard error]), V/F (32.9L 70.g-1 [37%]) and CL/F (23.1L h-1 .70kg-1[8.5%]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a power law parameterization centered around 105 mL.min.1.73m2. The effects of body weight were implemented using fixed allometric exponents centered around an adult weight of 70kg. Conclusion: Lisinopril dose and regimen adjustments for pediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Aims: Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing of propofol in this population. Methods: A non-linear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. Results: 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from three studies. Body weight (BW) of the pooled study population was 3.050 (0.580 – 11.440) kg, postmenstrual age (PMA) was 36.56 (27.00 – 43.00) weeks and postnatal age (PNA) was 1.14 (0 – 104.00) weeks (median and range). A three compartment structural model was identified and the effect of BW was modeled using fixed allometric exponents. Elimination clearance maturation was modeled accounting for the maturational effect on elimination clearance until birth (by GA) and postpartum (by PNA/GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.63 L min-1) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume (V1) in function of PNA improved the model fit. Conclusions: It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in V1. The developed model may serve as a prior for propofol dose finding in (preterm) neonates.