Utilization of an ex vivo human placental perfusion model to predict potential fetal exposure to carboplatin during pregnancy

Objective: The objective of this study was to determine the fetal drug compartment concentrations when various concentrations of carboplatin cross the placental-trophoblastic barrier and the effect on the fetal kidneys.

Study design: An ex vivo human placenta perfusion model was utilized. Term human placentae (n = 9) were collected immediately after delivery and then reperfused with plasma concentrations achieved with carboplatin an area under the curve of 5 (1000 ng/mL), 7.5 (5000 ng/mL), or 11 (11,000 ng/mL). Antipyrine was used as a reference compound. Samples were collected over 2 hours. Placental transfer was evaluated by computation of transport fraction and clearance index. Primary cells isolated by explant culture of 16-18 week old fetal organ tissues were incubated with carboplatin for up to 48 hours with untreated cell as controls. Immunohistochemical, flow cytometry analysis, and immunoblotting were applied for the expression of apoptosis-related proteins.

Results: Mean transport fractions for carboplatin at low, middle, and high concentrations were 0.05 ± 0.02, 0.04 ± 0.01, and 0.10 ± 0.01, respectively, with clearance indexes of 0.22 ± 0.01, 0.14 ± 0.08, and 0.50 ± 0.07, respectively. The fetal peak concentrations of carboplatin achieved were 61 ± 39 ng/mL (low), 375 ± 248 ng/mL (middle), and 2081 ± 529 ng/mL (high). Fetal kidney cells exposed to carboplatin showed a concentration-dependent increased expression of apoptosis-inducing factor and p53 apoptosis proteins and a time-dependent increase in expression Bax apoptosis protein expression. Apoptosis was confirmed at the high concentration by flow cytometry.

Conclusion: Doses of carboplatin up to an area under the curve of 7.5 were not associated with significant placental transfer, fetal exposure, or fetal toxic effects. This suggests it might not be necessary to empirically reduce carboplatin doses in pregnant women.