(S-110) Simulating Relative Infant Hydroxyurea Dose Through Breastfeeding Using a Semi-Mechanistic Population PK Model

Anhar Hosawi – University of Cincinnati / Cincinnati Children's; Irie Kei – Cincinnati Children's Hospital Medical Center; Min Dong – Cincinnati Children's Hospital Medical Center; Russell Ware – Cincinnati Children's Hospital Medical Center; Julie Ware – Cincinnati Children's Hospital Medical Center; Tomoyuki Mizuno – Cincinnati Children's Hospital Medical Center

Background: Hydroxyurea is the first-line treatment for sickle cell anemia in adults and children. As a ribonucleotide reductase inhibitor with theoretical risks, package inserts recommend discontinuation of either breastfeeding or hydroxyurea therapy in lactating women. To assess the potential infant’s hydroxyurea exposure through lactation, a semi-mechanistic population PK model of hydroxyurea in lactation was developed previously.1

Objective: This study aimed to simulate real-life lactation scenarios and estimate hydroxyurea relative infant dose (RID) using the previously established PK model, subsequently informing hydroxyurea dosing and lactation strategies to minimize the infant’s exposure.

Methods: The PK model used for simulations integrates a two-compartment model for plasma with a one-compartment model for breast milk.1 Monte Carlo simulations were performed using NONMEM and the mrgsolve package in R (4.3.1) to evaluate various scenarios of milk intake volume and feeding frequency for different age cohorts of infants (0-9 months old). A virtual cohort of 1,000 lactating women was generated based on the NHANES database to simulate hydroxyurea concentrations in breastmilk at a standard dose of 20 mg/kg/day. Age-dependent infant’s daily milk intake was estimated using the following equation according to a previous publication2:

Daily milk intake (ml/kg/day) = 160.39 * 0.232 / (0.232 – 0.00252) * (е-0.0025 * age – е -0.232 * age).
Per‑feed milk volume (mL/kg) was then calculated by dividing the daily intake by the typical number of feeds per day in each age cohort3. The hydroxyurea dose per feed (mg/kg) was obtained with the model‑predicted milk concentration and feed volume. The total daily dose (mg/kg/day) was compared with the RID thresholds of 5-10% (1 – 2 mg/kg/day of hydroxyurea).

Results: Milk intake increases from birth, peaking at 152.6 mL/kg/day around 19.7 days of age, followed by a gradual decline. Feeding frequency is age-dependent, with infants ≤3 months feeding more frequently than older infants. In the 1-month-old cohort, the estimated daily hydroxyurea dose through breastfeeding increases, in alignment with their milk intake and a feeding frequency of every 2 hours. For the entire age range, the simulated RIDs were below 10%, the safety threshold recommended by Hale’s Medications & Mothers’ Milk. For infants aged 1-3 months, RID was higher than 5% in approximately 30% of virtual patients. Avoiding lactation around the time of the highest milk concentration (Tmax, 1-1.5 hours post-dose) significantly reduced the RID.

Conclusion: This study demonstrates that the RID of hydroxyurea remains below 10% across all infant age groups (0-9 months). During early infancy (≤ 3 months), some infants may experience an RID exceeding the more restrictive threshold of 5%. However, this risk can be mitigated by adjusting the timing of dosing and breastfeeding to avoid lactation during the maternal Tmax window.

Citations: [1] Anhar Hosawi, Kei Irie, Min Dong, Russell Ware, Julie Ware, Tomoyuki Mizuno. Population Pharmacokinetic Modeling of Hydroxyurea in Plasma and Breast Milk in Lactating Women. American Conference on Pharmacometrics (ACoP) 2024.
[2] Yeung CHT, Fong S, Malik PRV et al. Quantifying breast milk intake by term and preterm infants for input into paediatric physiologically based pharmacokinetic models Matern Child Nutr 2020;16:e12938. First published on 2020/01/23, 10.1111/mcn.12938.
[3] Centers for Disease Control and Prevention (CDC). Infant and Toddler Nutrition: How Much and How Often to Breastfeed. Centers for Disease Control and Prevention. Accessed April 18, 2025.

Keywords: Hydroxyurea, Lactation, Modeling, Simulation