Model-Informed Evaluation of Hydroxyurea Exposure During Lactation.

Hydroxyurea is a cornerstone therapy for sickle cell anemia; however, evidence guiding its use during lactation remains limited. This study aimed to develop a population pharmacokinetic (PK) model to characterize hydroxyurea disposition in maternal plasma and breast milk, and to quantify infant exposure under clinically relevant breastfeeding scenarios. Population PK modeling was conducted using data from the HELPS study (NCT02990598) with nonlinear mixed-effects modeling. Maternal plasma PK parameters were first estimated using observed plasma concentration data, followed by estimation of parameters characterizing drug transfer into breast milk. Model-based stochastic simulations were performed across infant ages 0-9 months to evaluate exposure, expressed as the World Health Organization (WHO)-recommended relative infant dose (RID), with 10% as the consensus safety threshold. The model diagnostics demonstrated that both plasma and breast milk PK were adequately described by the model. Simulation analyses demonstrated that the estimated RID remained below 10% across all evaluated infant age groups. This integrated plasma-breast milk population PK model provides a quantitative framework to assess lactational drug exposure. The findings suggest that infant exposure to hydroxyurea through breastfeeding is unlikely to exceed the 10% safety threshold across all age groups (0-9 months), supporting continued maternal therapy during lactation with appropriate clinical oversight.