Evaluation of the maternal-fetal transfer of granisetron in an ex vivo placenta perfusion model

Purpose: The primary objective of this study was to determine the transfer of granisetron across the placental/trophoblastic barrier (PTB). Define the no effect dose level (NOEL) on the fetal tissues after in utero exposure to granisetron.

Methods: Term human placentas (N=8) were collected immediately after delivery. A single cotyledon from each placenta was localized, perfused and stabilized with physiologic Eagles minimal essential medium containing 3% bovine albumin and heparin. Granisetron was added to the maternal medium in two concentrations to mimic systemically achieved maternal peak concentrations following IV administration (50 ng/mL) and transdermal administration (5 ng/mL). To assess transfer and accumulation, fluid aliquots from both maternal and fetal compartments were collected for an open and closed systems. In vitro exposure of fetal derived cell lines with assessment of toxicity using flow cytometry and apoptotic protein ELISA.

Results: In the 50 ng/mL open model, maternal granisetron the mean peak concentration was 47.4 ± 14.8 ng/mL and a mean trough concentration of 27.0 ± 8.1 ng/mL with fetal side peak/trough concentrations of 7.1 ± 6.4 ng/mL and 4.8 ± 4.4 ng/mL respectively. However, in the 5 ng/mL model, the maternal granisetron peak/trough concentrations were 5.0 ± 0.5 and 3.7 ± 0.6 ng/mL and there was no detectable drug in the fetal compartment. The mean granisetron clearance index was 0.70 ± 0.68. No significant difference was observed in apoptosis at 3 ng/mL.

Conclusions: Transplacental passage of granisetron was incomplete at high concentrations that would be achieved with intravenous dosing in the pregnant patient. Higher concentrations have potential to induce up to 10% apoptosis in cardiac tissue however the clinical significance needs further evaluation. At concentrations similar to those achieved with transdermal administration of granisetron there was no transplacental passage of granisetron and were below the NOEL thus would be safe during pregnancy.