Both favorable pregnancy outcomes and fetal abnormalities have been associated with the use of tyrosine kinase inhibitors (TKIs) during pregnancy. The placental transfer of TKIs in humans is poorly understood. We observed women with chronic myeloid leukemia who used imatinib or nilotinib during the late pregnancy stages. The newborns had no birth abnormalities. We evaluated the drug concentrations in maternal blood, umbilical cord blood, and placental samples collected during labor. We found limited placental transfer of the TKIs. The fetal/maternal concentration ratio ranged from 0.5 to 0.58 for nilotinib and from 0.05 to 0.22 for imatinib. The placental/maternal ratio was higher for imatinib than for nilotinib. Theoretical pharmacokinetic modeling of passive placental crossing was insufficient to predict the in vivo data because the calculated fetal/maternal ratio was close to 1 for both drugs. We propose that active placental transport contributes to fetal protection against TKI exposure during pregnancy.

Breastfeeding in patients with chronic myeloid leukaemia (CML) who take tyrosine kinase inhibitors (TKIs) is not recommended but interruption of TKI treatment may cause the loss of remission. We observed the kinetics of the leukaemic clone in 3 women with CML in accordance with treatment interruptions for pregnancy and breastfeeding. The concentrations of nilotinib and imatinib in maternal milk were measured when the breastfeeding period was over. Nilotinib transfer into human breast milk was demonstrated for the first time and had a maximum concentration (Cmax) 129 ng/ml after 4 hours of the drug intake at a dose of 400 mg. The Cmax of imatinib in maternal milk ranged from 420 to 1411 ng/ml after 4-8 hours of the drug intake at a dose of 400-600 mg. Breastfeeding without TKI treatment may be safe with molecular monitoring, but preferably in those patients with CML who have durable deep molecular response.