Clinical trial NCT02020083: Placental Transfer of Tenofovir
Official title: Study of Placental Transfer of Tenofovir and Its Factors of Variability Using the Human Placental Perfusion Model
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pregnant Women
Keywords: VIH ; Placental transfer ; Tenofovir ; Emtricitabine ; Membrane transporter
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2013-12-24
Enrollment: 369
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pregnant women (at term \>37 to 41 weeks of gestational age) without complications during pregnancy

Brief summary: The purposes of this study are to determine whether transporters expression levels and drug interaction between TDF and FTC could contribute to modulate the placental transfer of this drug or. To test this hypothesis, an ex vivo model known as "the perfused ex vivo cotyledon model" allows to reproduce the conditions of the third trimester of pregnancy

Detailed description: Nowadays, mother-to-child HIV transmission is the main cause of paediatric HIV infections. Yet, this way of transmission is effectively limited by the use of antiretroviral therapies during pregnancy in HIV infected women. The study TEmAA (ANRS 12109) we conducted allowed us to suggest a therapeutic scheme of administration of the association tenofovir disoproxil fumarate (TDF) - emtricitabine (FTC) to reduce the risk of postpartum resistance that may occur with the administration of a single dose of nevirapine before delivery. However, we also observed a large interindividual variability of TDF in vivo placental transfer that remained unexplained. Placental membrane transporters, including efflux transporters belonging the ABC transporter superfamily and uptake transporters, may constitute a source of variability. In this case, we showed such an association for maraviroc with a significant inverse correlation between its clearance index and the placental expression level of several efflux transporters of the ABCC/MRP family. Regarding TDF, it has been shown that this drug is a substrate of several efflux transporters (ABCC2/MRP2, ABCC4/MRP4, ABCC10/MRP7) and an uptake transporter (hOAT3). As these transporters are expressed on the placental barrier, it may be hypothesized that their expression levels could contribute to modulate the placental transfer of this drug. To test this hypothesis, an ex vivo model known as "the perfused ex vivo cotyledon model" allows to reproduce the conditions of the third trimester of pregnancy. Our first aim is to evaluate the potential effect of ABCC2, ABCC4, ABCC10 and hOAT3 placental expression on TDF placental transfer (First year). We also want to investigate whether a potential interaction between TDF and FTC could take part to variability.

Eligibility criteria: Inclusion Criteria:

* Major Patients \> or = 18 years old
* At term between 37 and 41 weeks of gestational age
* Uncomplicated pregnancy
* Informed Consent Form signed

Exclusion Criteria:

* Women HIV+, HBV+ or HBC+
* Women with cardiovascular diseases such as diabetes or preeclampsia, IUGR
* Women who had taken medications during pregnancy

Primary outcomes:
measure: Determination of ABC transporters gene expression levels by quantitative RT-PCR
timeFrame: 1 hour
Secondary outcomes:
measure: Fetal transfer rate (%)of emtricitabine alone, or Tenofovir alone, or in association
timeFrame: 3 hours
Other outcomes:
Locations:
city: Paris
country: France
facility: Maternité de Port Royal
Study officials:
affiliation: APHP
name: Jean Marc Treluyer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hirt D, Urien S, Ekouevi DK, Rey E, Arrive E, Blanche S, Amani-Bosse C, Nerrienet E, Gray G, Kone M, Leang SK, McIntyre J, Dabis F, Treluyer JM; ANRS 12109. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009 Feb;85(2):182-9. doi: 10.1038/clpt.2008.201. Epub 2008 Nov 5.
citation: Vinot C, Gavard L, Treluyer JM, Manceau S, Courbon E, Scherrmann JM, Decleves X, Duro D, Peytavin G, Mandelbrot L, Giraud C. Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression. Antimicrob Agents Chemother. 2013 Mar;57(3):1415-20. doi: 10.1128/AAC.01821-12. Epub 2013 Jan 7.