Placental disposition of the immunosuppressive drug tacrolimus in renal transplant recipients and in ex vivo perfused placental tissue

J.J.M Freriksen,D Feyaerts,P.H.H Van Den Broek,O.W.H Van Der Heijden,J Van Drongelen,H.W Van Hamersvelt,F.G.M Russel,R.G Van Der Molen,R Greupink

doi:10.1016/j.ejps.2018.04.017

Abstract

Currently, tacrolimus is the most potent immunosuppressive agent for renal transplant recipients and is commonly prescribed during pregnancy. As data on placental exposure and transfer are limited, we studied tacrolimus placental handling in samples obtained from renal transplant recipients. We found transfer to venous umbilical cord blood, but particularly noted a strong placental accumulation. In patient samples, tissue concentrations in a range of 55–82 ng/g were found. More detailed ex vivo dual-side perfusions of term placentas from healthy women revealed a tissue-to-maternal perfusate concentration ratio of 113 ± 49 (mean ± SEM), underlining the placental accumulation found in vivo. During the 3 h ex vivo perfusion interval no placental transfer to the fetal circulation was observed. In addition, we found a non-homogeneous distribution of tacrolimus across the perfused cotyledons. In conclusion, we observed extensive accumulation of tacrolimus in placental tissue. This warrants further studies into potential effects on placental function and immune cells of the placenta.

Highlights

The incidence of pregnancy in the renal transplant patient population is relatively high and increasing (OPTN/SRTR, 2014; McKay & Josephson, 2006)
Data on fetal drug exposure are limited to either case reports or pharmacoepidemiological studies describing pregnancy outcome after kidney transplantation under tacrolimus or cyclosporine A, as for instance performed by the National Transplantation Pregnancy Registry (NTPR) (Coscia et al, 2010)
In a study performed by Jain et al, who focused on liver transplant patients, a 3-fold higher tacrolimus concentration in placental tissue compared to maternal plasma levels was reported (Jain et al, 1997)

Summary

Introduction

The incidence of pregnancy in the renal transplant patient population is relatively high and increasing (OPTN/SRTR, 2014; McKay & Josephson, 2006). Data on fetal drug exposure are limited to either case reports or pharmacoepidemiological studies describing pregnancy outcome after kidney transplantation under tacrolimus or cyclosporine A, as for instance performed by the National Transplantation Pregnancy Registry (NTPR) (Coscia et al, 2010). This large voluntary registry included almost 2000 pregnancies in female kidney recipients in the period 1990–2010 in North America and reported that of all neonates born, 53% was premature and 46% had a low birthweight (< 2500 g), which is significantly higher than the general prevalence in the US in 2010 of approximately 12% and 8%, respectively. The limited available literature does not report any clinically relevant differences in pregnancy outcome when comparing immunosuppressive drugs (Perales-Puchalt et al, 2012)

Methods

Results

Conclusion