Using Cotyledon Perfusion to Study Drugs Transfer Across the Placenta

Overview

Drug prescriptions are usual during pregnancy however women and their fetuses still remain an orphan population with regard to drugs efficacy and safety clinical studies. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. The aim of the study is to study the drug transfer using human placenta after delivery.

Full Title of Study: “Ex Vivo Study of Drugs Transfer Across the Placenta”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: May 2030

Detailed Description

For ethical reasons, pregnant woman are not included in clinical trials so that data regarding safety and efficacy of many drugs are scarce. It is known that xenobiotics across the placental barrier but studies regarding quantity and mechanisms of this transfer remain insuffisant. Among the different methodologies to evaluate drug transfer, perfusion of human cotyledon is one of the most relevant ones. The two sides of the cotyledon, fetal and maternal ones, are perfused within the hour after delivery with EARLE medium in a double closed circuit. The studied drug (it can be any drug given to pregnant mothers) and antipyrine (the control molecule) are added at the beginning of the three hours perfusion realized at 37°C, with maternal flow rate of 12ml/min and fetal one of 6ml/min. Samples are collected along the perfusion and the drugs dosage will be done in the pharmacology department of Cochin Hospital. Tissues of the cotyledon will be also collected to study the proteins, and ARNs expressed. The drug concentrations will be analyzed by calculating fetal to maternal concentrations ratios and a fetal transfer rate (fetal drug quantity on total drug quantity at the end of the perfusion). Then modelling on Monolix software will be done to estimate the transfer constants across the two compartments. Modelling will allow to estimate the interindividual variability and to test covariables like sex, gestation duration, genetics, or protein expression. Proteins will be studied by an appropriated method (western blot, or proteomic analysis). The genetics study will consist in candidate gene approach. Polymorphisms will be chosen in genes coding for transporters or enzymes or their regulators.

Interventions

  • Other: Placenta perfusion
    • Placenta perfusion in double closed circuit, during 3 hours

Arms, Groups and Cohorts

  • Pregnant mothers
    • Pregnant mothers who have a normal pregnancy

Clinical Trial Outcome Measures

Primary Measures

  • Fetal transfer rate
    • Time Frame: At 180 minutes (end of the perfusion)
    • Quantity of drug transferred into fetal compartment/ quantity of drug in the two compartments *100

Secondary Measures

  • Ratio of concentrations
    • Time Frame: At 180 minutes (end of the perfusion)
    • Fetal concentration / maternal concentration *100

Participating in This Clinical Trial

Inclusion Criteria

  • pregnant women older than 18 years
  • non pathological pregnancy
  • term between 37th and 41th amenorrhea week
  • single pregnancy,
  • patient who has given her consent for genetic

Exclusion Criteria

  • diabetes-like vascular disease
  • pre-eclampsia
  • Delayed growth in utero (can affect placental circulation)
  • maternal serology HIV+, BHV+, CHV+
  • Patient on long-term treatment
  • patient under tutorship or curatorship
  • patient who has not given her consent

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Jean-Marc TRELUYER, Pr, 00 33 1 58 41 28 85, jean-marc.treluyer@parisdescartes.fr

References

Schneider H, Panigel M, Dancis J. Transfer across the perfused human placenta of antipyrine, sodium and leucine. Am J Obstet Gynecol. 1972 Nov 15;114(6):822-8.

Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011 Jul;90(1):67-76. doi: 10.1038/clpt.2011.66. Epub 2011 May 11. Review. Erratum in: Clin Pharmacol Ther. 2011 Sep;90(3):479.

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