Tamara van Donge

Physiological changes during pregnancy and neonatal life 29 2 increased from 0.068 g/L at 20 weeks of gestation to 0.23 g/L at 40 weeks of gestation. In addition, the placental transfer layer is the thinnest just before birth, reducing the expression of certain efflux transporters such as P-glycoprotein. Therefore, the transfer of drugs and the fetal exposure may be maximal at term, as compared to earlier gestational ages (Figure 1). 24 A 29.4-fold increase in the large intestinal volume between 20 and 40 weeks of gestation has been demonstrated. 26 It has also been shown that hepatic organogenesis begins from the fetal mesoderm and endoderm during the fourth week of gestation and transcription of hepatic enzymes involved in drug metabolism, has been detected at eight to ten weeks of gestation. 27 Focusing on the volume of the kidney in a period between 20 weeks and 40 weeks of gestation, the volume increased from 3.39 ml to 31.21 ml. 26 During pregnancy, the homeostasis is assigned to the placenta and the main task of the fetal kidney is the excretion of urine (hypotonic) as a major component of the amniotic fluid. This might explain why the glomerular filtration rate in the fetus is low, even at the end of gestation (Figure 1). 28 Because of ethical and practical constraints of performing clinical trials in this subpopulation, PBPK modeling could provide mechanistic understanding of the fetal drug exposure and might be able to predict the drug exposure during the entire pregnancy until birth. Several research groups have tried to quantify the placental drug transfer to the fetus. Although many of the approaches are substance-specific and therefore cannot be used for other compounds, these are valuable contributions. 26,29-31 We expect that in the near future more knowledge will be gained in fetal pharmacotherapy and that PBPK modeling will contribute to this. A recent publication provided understanding on the exposure of ceftazidime in both, the pregnant woman and the fetus by the development of a population PK model. 32 Ceftazidime has been frequently used in pregnant women to treat intrauterine or urinary tract infections. This antibiotic is hydrophilic causing it to mainly distribute into tissues with high water content (e.g. kidneys) and it is purely eliminated by glomerular filtration. Since ceftazidime crosses the placenta, concentrations in the plasma of the pregnant woman and in amniotic fluid are similar. This PK model has provided insights on the pharmacokinetics of ceftazidime in pregnant women and newborns. Low drug clearance during the first days of life of newborns is most likely due to the reduced number of perfused glomeruli and reduced renal blood flow. Performing clinical trials in newborns is especially cumbersome, not only because of ethical considerations but also due to practical challenges such as limited amount of blood and the corresponding inability to collect multiple samples. Currently, biomarkers to assess fetal drug exposure gain attention; examples are neonatal hair tests or placental