Tamara van Donge

Chapter 2 32 weight changes in healthy neonates and quantified key factors (maternal and neonatal) influencing individual weight profiles during the first seven days of life. It was illustrated that birth weight increases more with advancing gestational age and that boys weigh more than girls at birth. In addition, it was showed that weight gain is influenced by gestational age and that birth weight increases with the maternal age. 45 Optimize and personalize pharmacotherapy during pregnancy and neonatal life In this new era which is highlighted by technology and innovative approaches it should not be the case that pregnant women and their newborns are still dependent on off-label drug use. By incorporating knowledge on the physiological changes that happen during these life changing periods, we can assess the influence on pharmacokinetic profiles and adjust dosing recommendations, ensuring a safe and effective treatment. Only in the rare circumstance that there is similarity between adults and infants in disease, the mechanism of action of the drug, and the PK/PD relationships, it is justified and allowed to extrapolate the pediatric dose from adult dosages. 46 Otherwise it is required to address all these components before extrapolating pediatric dose from adult standard of care. Modeling and simulation can not only be applied in order to gain insights in the PK of drugs in this special populations, it can also support and optimize the design of pediatric studies. When designing a new pediatric pharmacokinetic/pharmacodynamic study it is important to know how many samples per patient are required, what the best sampling times are, and how many patients are needed to obtain a statistically powered estimation of the PK/PD parameters. After obtaining clinical data, the first step for PK/PD model-based guidance is to select the appropriate target in the population of interest, such as a desired plasma concentration, target exposure (area under the curve, AUC), time above target exposure or other measure matrices. Thereafter, one can define the dosage regimen to best achieve this target while taking in to account various factors which influence the disposition of the drug (demographic characteristics such as gestational age, weight or postnatal age). Development of pregnancy PBPK models makes it possible to assess drug exposure in all trimesters and investigate multiple dosing strategies. Although over the recent years a lot of progress is made with pregnancy PBPK models, knowledge gaps still remain. An integrated feto-maternal PBPK model would be able to examine fetal drug therapy during pregnancy. In order to develop such a complex model, quantitative information on system-