Tamara van Donge

Chapter 2 28 prevent or treat conditions that develop during pregnancy and to guarantee the health of the woman, although in some cases, the target of the treatment is the fetus, as is the case with the prevention of HIV transmission. 25 Regardless whether the fetus is the actual target of pharmacological therapy, the fetus is exposed to almost every drug taken by the pregnant woman. It needs no clarification that the ability to evaluate the fetal exposure to drugs, either their efficacy but most importantly, their risk of toxicity, is imperative. Pregnancy Fetus Newborn Physiological changes Impact on pharmacokinetics ADME ▪ Gastrointestinal motility ↑ ▪ Gastric pH ↓ ▪ Altered drug bioavailaibility ▪ Delayed time to reach peak levels (po administration) k a ▪ Total body water and plasma volume ↑ ▪ Adipose compartiment ↑ ▪ ↑ V d for hydrophilic drugs ▪ ↑ V d for lipophilic drugs V d ▪ Cardiac output and blood flow ↑ ▪ Glomerular filtration rate ↑ ▪ Altered activity of drug metabolizing enzymes ▪ ↑ Elimination ▪ ↑ Renal clearance ▪ Affecting bioavailability & hepatic clearance CL Physiological changes Impact on pharmacokinetics ADME ▪ Fetal urine enters amniotic fluid ▪ Fetal plasma pH < maternal plasma pH ▪ Reabsorption of excreted drugs by swallowing ▪ ↑ accumulation in fetal plasma ( ↓ backtransfer to maternal plasma due to ↑ ionization on fetal side) k a ▪ Albumin and α 1 -glycoprotein levels ↑ with GA ▪ Thickness of placental layer ↓ with GA ▪ ↑ Active drug amount (relative low protein levels) ▪ ↑ Drug transfer and fetal drug exposure V d ▪ Expression of metabolizing enzymes ▪ Kidney volume ↑ ▪ ↓ Metabolizing capacity compared to mother ▪ Low glomerular filtration rate (immature kidney) CL Physiological changes Impact on pharmacokinetics ADME ▪ Changes of gastric acid production remain unclear ▪ Food type influences gastric emptying ▪ At birth gastric pH is neutral (due to amniotic fluid) ▪ Gastric emptying time water > milk > solid food k a ▪ Total body water ↑ ▪ Adipose tissue and muscle mass ↓ ▪ Protein binding ↓ , relative brain weight and cerebral:systemic blood flow ↑ ▪ ↑ V d for hydrophilic drugs ▪ ↓ V d for lipophilic drugs ▪ ↑ Drug concentrations in brain V d ▪ Renal blood flow ↑ ▪ ↑ Glomerular filtration rate CL Figure 1: Schematic overview representing physiological changes and their corresponding impact on pharmacokinetics in pregnant women, their fetus and newborns. Data retrieved from literature. 2,7,26,27,29,36-38,47,48 ADME: absorption, distribution, metabolism and excretion, k a , absorption rate, V d : volume of distribution, CL: clearance, GA: gestational age. As it is currently impossible to study drug exposure prior to birth and even at the time of birth the assessment of fetal exposure to drugs is limited to a single measurement of umbilical cord plasma concentration, which unfortunately does not reflect fetal drug exposure. 26 A recent review showed that fetal serum albumin concentrations, in contrast to serum albumin concentrations of pregnant woman, increase with advancing gestational age (GA), although they remain relatively low compared to adult values. 26 Fetal serum albumin levels reach 22.1 g/L at week 20 of gestation and 38.3 g/L at week 40 of gestation, a 1.73-fold increase. 26 Alpha 1 -glycoprotein, one of the major drug binding proteins, was