Maternal Ezetimibe Concentrations Measured in Breast Milk and Its Use in Breastfeeding Infant Exposure Predictions.

BACKGROUND:Lactating mothers taking ezetimibe, an antihyperlipidemic agent, may be hesitant to breastfeed despite the known benefit of breastfeeding to both mother and infant. Currently, no data exist on the presence or concentration of ezetimibe and its main active metabolite, ezetimibe-glucuronide (EZE-glucuronide), in human breast milk. METHODS:Voluntary breast milk samples containing ezetimibe and EZE-glucuronide were attained from lactating mothers taking ezetimibe as part of their treatment. An assay was developed and validated to measure ezetimibe and EZE-glucuronide concentrations in breast milk. A workflow that utilized a developed and evaluated pediatric physiologically based pharmacokinetic (PBPK) model, the measured concentrations in milk, and weight-normalized breast milk intake volumes was applied to predict infant exposures and determine the upper area under the curve ratio (UAR). RESULTS:Fifteen breast milk samples from two maternal-infant pairs were collected. The developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed an analytical range of 0.039-5.0 ng/mL and 0.39-50.0 ng/mL for ezetimibe and EZE-glucuronide, respectively. The measured concentrations in the breast milk samples were 0.17-1.02 ng/mL and 0.42-2.65 ng/mL of ezetimibe and EZE-glucuronide, respectively. The evaluated pediatric PBPK model demonstrated minimal exposure overlap in adult therapeutic dose and breastfed infant simulated area under the concentration-time curve from time zero to 24 h (AUC24). Calculated UAR across infant age groups ranged from 0.0015 to 0.0026. CONCLUSIONS:PBPK model-predicted ezetimibe and EZE-glucuronide exposures and UAR suggest that breastfeeding infants would receive non-therapeutic exposures. Future work should involve a 'mother-infant pair study' to ascertain breastfed infant plasma ezetimibe and EZE-glucuronide concentrations to confirm the findings of this work.