Physiologically Based Pharmacokinetic Modelling of Hydroxyurea in Patients with Sickle Cell Disease: A Special Focus on Lactating Women and Breastfed Infants to Inform Safe Dosing and Breastfeeding Strategies

<b>Background/Objectives</b>: Hydroxyurea is currently the standard disease-modifying therapy for reducing sickle cell disease (SCD) complications; however, drug labels currently advise discontinuation of breastfeeding during hydroxyurea therapy due to limited human data on the risk of hydroxyurea exposure in breastfed neonates. <b>Methods</b>: A physiologically based pharmacokinetic (PBPK) model for hydroxyurea was built and verified with data from non-lactating adult patients with SCD. The model was then extended to predict hydroxyurea in nursing and in paediatric populations. Predictions were compared to the observed data. <b>Results</b>: The PBPK model predictions for hydroxyurea pharmacokinetics described the observed data in both adult and paediatric subjects with SCD. Observed concentration profiles were within the 5th-95th prediction intervals, and predicted PK parameters were within 2-fold of the observed values. The predicted milk-to-plasma ratio was 0.8. Neonatal exposure to hydroxyurea via breast milk as a percentage of maternal exposure increased from 0.6% at 1 day to 10% at the 4th week postpartum before declining to 5%, 3%, and 2% at 6, 9, and 12 months postpartum, respectively. <b>Conclusions</b>: About 56% of total milk hydroxyurea exposure is within the first 3 h of post-maternal dose. Disposal of this early milk would reduce the exposure of breastfed children. The reduction in exposure is especially pronounced around the first 1 month postpartum. Lactation PBPK models offer a physiological approach to assess real-life scenarios that are difficult to investigate in clinical studies and provide useful results for future clinical study design and clinical recommendations. This was exemplified with hydroxyurea in the current work.