Transplacental Transfer of Paclitaxel, Docetaxel, Carboplatin, and Trastuzumab in a Baboon Model

Calsteren, Kristel Van MD, PhD*†; Verbesselt, Rene PhD‡; Devlieger, Roland MD, PhD§; De Catte, Luc MD, PhD§; Chai, Daniel C. DVM∥; Van Bree, Rieta LT†; Heyns, Liesbeth MSc*†; Beijnen, Jos PhD¶; Demarsin, Sonia LT‡; de Bruijn, Ernst PhD**; de Hoon, Jan MD, PhD‡; Amant, Frédéric MD, PhD*†

International Journal of Gynecological Cancer:
doi: 10.1111/IGC.0b013e3181fb18c8
Basic Science
Abstract

Background: The paucity of data on fetal effects of prenatal exposure to chemotherapy prompted us to study the transplacental transport of commonly used anticancer agents in a pregnant baboon model.

Methods: Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/m2 [n = 2]; docetaxel, 100 mg/m2 [n = 2]; paclitaxel, 175 mg/m2 with carboplatin, area under the curve of 6 at standard dosage [n = 2] and 50% dosage [n = 1]; docetaxel, 75 mg/m2 with carboplatin, area under the curve 6 [n = 1]; and docetaxel, 75 mg/m2 with trastuzumab, 8 mg/kg [n = 1]). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay.

Results: Fetal plasma concentrations of carboplatin averaged 57.5% (14.2%) of maternal concentrations (n = 7). Fetal plasma concentrations were 1.5% (0.8%) of maternal concentrations (n = 7). Immediately after ending the infusion, paclitaxel was not detectable in fetal tissues, whereas, after 3 hours, fetal tissues contained 15% of maternal tissue concentrations.

Docetaxel could not be detected in fetal blood samples (n = 9). In the first 3 hours after docetaxel infusion, fetal tissues contained 5.0% to 50.0% of maternal tissue concentrations, whereas equal fetal and maternal tissue concentrations were found after 26 and 76 hours.

The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration.

Conclusion: Variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. These data are important when cancer treatment is considered during pregnancy and underline the need for long-term follow-up of children after prenatal exposure to these cytotoxic agents.

Author Information

*Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, †Department of Obstetrics & Gynecology, **Laboratory of Experimental Oncology, Laboratory ofExperimental Gynecology, ‡Center for Clinical Pharmacology, and §Department of Obstetrics & Gynecology, Division of Prenatal Medicine, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium; ∥Department of Reproductive Biology, Institute of Primate Research, Nairobi, Kenya; and ¶Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.

Received May 24, 2010, and in revised form August 15, 2010.

Accepted for publication September 5, 2010.

Address correspondence and reprint requests to Frédéric Amant, MD, PhD, Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: Frederic.amant@uz.kuleuven.ac.be.

This research is supported by the Research Foundation-Flanders (FWO; grant number G.0358.06), Stichting tegen Kanker (grant number SCIE2006-17), Research Fund-K.U. Leuven (grant number OT/07/053), Clinical Research Fund-UZ Gasthuisberg, and FOD (grant number NKP 29 038).

F.A. is a clinical researcher for Research Foundation-Flanders (FWO); K.V.C. is an aspirant for Research Foundation-Flanders (FWO); R.D.V. is a clinical researcher for Clinical Research Fund-UZ Gasthuisberg.

Copyright © 2010 by IGCS and ESGO