Tacrolimus placental transfer at delivery and neonatal exposure through breast milk

Abstract

Aim(s): The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk.

Methods: Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject.

Results: Mean (±SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng ml(-1)) were 71 ± 18% (range 45-99%) of maternal concentrations (9.0 ± 3.4 ng ml(-1)). The mean umbilical cord venous plasma (0.09 ± 0.04 ng ml(-1)) and unbound drug concentrations (0.003 ± 0.001 ng ml(-1)) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose.

Conclusions: Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher haematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.

Keywords: breast milk; neonatal exposure; placental transfer; pregnancy; tacrolimus; unbound drug concentration.

Figure 1

Tacrolimus venous umbilical cord blood : maternal blood, venous umbilical cord plasma : maternal plasma and venous umbilical cord unbound : maternal unbound concentration ratios in eight patients, shown by the time after last dose of tacrolimus to blood sampling. For each ratio, the different data points represent an observation in a different subject. •, venous cord blood : maternal blood (n = 7); ▵, venous cord plasma : maternal plasma (n = 6); , venous cord unbound : maternal unbound (n = 5)

Figure 2

Tacrolimus maternal blood : plasma (n = 7), venous umbilical cord blood : plasma (n = 6) concentration ratios in patients, taking tacrolimus at the time of delivery (A) and the calculated K_bc/p, the tacrolimus partitioning ratio between blood cells and plasma, in maternal blood (n = 7) and venous umbilical cord blood (n = 6) (B). The horizontal lines represent the mean ratios. A) □, maternal blood : maternal plasma; ▴, venous cord blood : venous cord plasma; B) □, maternal blood K_bc/p; ▴, Venous Cord Blood K_bc/p

Figure 3

Tacrolimus concentration (logarithmic scale) in maternal blood, plasma and breast milk (A) and steady-state unbound tacrolimus concentrations in maternal plasma and breast milk (B) of one subject over a single dosing interval. The subject was treated with 1.5 mg of tacrolimus twice daily for immunosuppression. A) , milk; , plasma; , blood; B) , milk unbound drug; , plasma unbound drug