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Transplacental Transfer of Drugs Used in Pregnant Women

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02622802
Recruitment Status : Completed
First Posted : December 7, 2015
Last Update Posted : May 3, 2017
Information provided by (Responsible Party):
Kristel Van Calsteren, MD PhD, University Hospital, Gasthuisberg

Brief 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.

Condition or disease Intervention/treatment Phase
Pregnancy Drug: paracetamol Drug: Erythromycin Drug: Azithromycin Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 250 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Transplacental Transfer of Drugs Used in Pregnant Women
Actual Study Start Date : November 2012
Actual Primary Completion Date : December 2016
Actual Study Completion Date : May 2017

Arm Intervention/treatment
Experimental: ex-vivo placenta perfusion
ex vivo placenta perfusion study with exposure to paracetamol, erythromycin and azithromycin
Drug: paracetamol
In an ex vivo placenta perfusion study, placental tissue is exposed to paracetamol
Other Names:
  • Paracetamol Sigma Aldrich
  • acetaminophen

Drug: Erythromycin
In an ex vivo placenta perfusion study, placental tissue is exposed to erythromycin
Other Name: Erythromycin Sigma Aldrich

Drug: Azithromycin
In an ex vivo placenta perfusion study, placental tissue is exposed to azithromycin
Other Name: Azithromycin Sigma Aldrich

Primary Outcome Measures :
  1. Transplacental transfer rate of drugs and their metabolites measured by comparing the concentrations in simultaneously collected samples from the maternal and fetal compartment in a human ex-vivo placenta perfusion model [ Time Frame: 12 months for each drug ]
    the drug concentrations will be determined by high performance liquid chromatography and mass spectrometry

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • informed consent has been signed
  • (placenta of a) pregnant women with an uncomplicated pregnancy and delivery

Exclusion Criteria:

  • use of medication during pregnancy
  • hypertension, diabetes
  • smoking

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02622802

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University Hospital Gasthuisberg
Leuven, Belgium, 3000
Sponsors and Collaborators
University Hospital, Gasthuisberg
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Principal Investigator: Kristel Van Calsteren, MD PhD University Hospital Gasthuisberg Leuven
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Responsible Party: Kristel Van Calsteren, MD PhD, Prof Dr, University Hospital, Gasthuisberg Identifier: NCT02622802    
Other Study ID Numbers: PPS201210
2012-004580-51 ( EudraCT Number )
First Posted: December 7, 2015    Key Record Dates
Last Update Posted: May 3, 2017
Last Verified: May 2017
Keywords provided by Kristel Van Calsteren, MD PhD, University Hospital, Gasthuisberg:
ex-vivo placenta perfusion
transplacental transfer
Additional relevant MeSH terms:
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Erythromycin Estolate
Erythromycin Ethylsuccinate
Erythromycin stearate
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Gastrointestinal Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action