Transplacental Transfer of Drugs Used in Pregnant Women
Condition: Pregnancy
Study type: Interventional

Summary: 
      The most important guideline for drug prescription concerning pregnant women is 'drugs should
      be given only if the maternal benefits outweigh the potential risk to the fetus'. However,
      poor data is available on maternal drug disposition and transfer through the placenta, so the
      evidence available for decision making in clinical practice is weak.

      An ex-vivo placenta perfusion model will be used to explore the mechanisms governing
      differences between fetal and maternal drug exposure. The expression of placental
      transporters and cytochrome P450 (CYP) enzymes will be investigated in primary placenta cell
      culture and placental biopsies from different gestational stages to learn how the placental
      drug transfer and disposition is regulated.

      The investigators choose to examine the transfer of paracetamol, erythromycin and
      azithromycin because these drugs are commonly used in human pregnancies and have different
      metabolic pathways.
    

Detailed description: 
      1. Background While many drugs are administered to pregnant women, only poor data exist to
           determine a therapeutically optimal and safe drug treatment in this patient population.

           The general advise on the use of medicines in pregnancy is that you can only prescribe
           drugs to pregnant women if the benefits for the mother outweigh the risks for the fetus.
           The problem is that for most medicines safety data are lacking. Most drug effects are
           dose dependent. So the first step to examine potential fetotoxicity is to test
           transplacental transfer of drugs.

           Placental transfer from the maternal to the fetal side occurs primarily via passive
           diffusion, the physicochemical properties of drugs such as lipid solubility, polarity
           and molecular weight primarily determine the rate of transfer across the placenta.
           According to membrane permeability properties, low-molecular-weight, lipid-soluble,
           unbound and unionized compounds can easily cross the human placenta. In addition, some
           drugs are pumped across the placenta by various active transporters located on both the
           fetal and maternal side of the trophoblast layer. The most important transporters are
           P-glycoprotein (P-gp, encoded by the multidrug resistance (MDR)1 gene), Breast cancer
           resistance protein (BCRP) and multidrug resistance-associated protein (MRP) 1-3 and 5.

           The transfer of foreign chemicals across the placenta can also be modified by metabolism
           in the placenta itself. The human placenta contains multiple enzyme systems, like CYP2E1
           and CYP3A4.

        2. Aim & methods:

      The aim of this study is to determine fetal drug concentrations of paracetamol, erythromycin
      and azithromycin by transplacental transport in an ex-vivo placenta perfusion model.
      Simultaneously collected maternal and fetal drug plasma levels will be compared to assess
      fetal drug levels based on maternal drug plasma levels.

      Moreover, the transporter and metabolizing activity of the trophoblast cells will be examined
      in a primary human trophoblast culture, and expression of enzymes and transporters will be
      evaluated at different gestational ages in human placenta biopsies.

      Medicines: The investigators choose to examine the transfer of paracetamol, erythromycin and
      azithromycin because these drugs are commonly used in human pregnancies.

      Since the ORACLE trial, erythromycin is in Belgium the first choice treatment in patients
      with preterm rupture of membranes, despite the fact that the pharmacokinetics (PK) of this
      drug has been hardly studied in pregnant women. Erythromycin is unstable under acidic
      conditions while azithromycin is a semi-synthetic macrolide, with a better gastro-intestinal
      tolerability and tissue penetration than erythromycin and an excellent activity against
      sexually transmitted pathogens, especially Chlamydia trachomatis. Because of these
      characteristics more physicians start to switch to azithromycin even without PK data
      available in pregnancy.

      Paracetamol (acetaminophen) is used as first choice painkiller in pregnancy, but also for
      this drug surprisingly few PK data are available.
    

Intervention name(s): paracetamol; Erythromycin; Azithromycin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): In an ex vivo placenta perfusion study, placental tissue is exposed to paracetamol; In an ex vivo placenta perfusion study, placental tissue is exposed to erythromycin; In an ex vivo placenta perfusion study, placental tissue is exposed to azithromycin
Other intervention name(s): Paracetamol Sigma Aldrich; acetaminophen; Erythromycin Sigma Aldrich; Azithromycin Sigma Aldrich
Intervention MeSH terms: Acetaminophen; Azithromycin; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin stearate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: ex-vivo placenta perfusion; transplacental transfer; paracetamol; erythromycin; azithromycin