Population Pharmacokinetic Modeling of Hydroxyurea in Plasma and Breast Milk in Lactating Women
Authors: Hosawi Anhar , Irie Kei , Dong Min , Ware Russell , Ware Julie , Mizuno Tomoyuki 
Published: February 2025

Background: Sickle Cell Anemia (SCA) is a prevalent inherited blood disorder affecting millions of people worldwide [1]. Improved treatment has led to more SCA patients reaching childbearing age, resulting in a projected 25% increase in SCA births by 2050 [2]. Hydroxyurea is the primary pharmacotherapy for SCA, with evidence supporting early initiation of treatment as early as 9 months [2]. However, it is common practice to discontinue hydroxyurea during pregnancy and lactation due to theoretical risks [2, 3]. This discontinuation can worsen symptoms and increase health risks for both the mother and the infant during pregnancy and postpartum [2]. Thus, understanding hydroxyurea treatment during pregnancy and lactation is crucial. Our study aimed to develop a semi-mechanistic population pharmacokinetics (PK) model to describe hydroxyurea's plasma and breast milk profile during lactation. Method: Plasma and milk hydroxyurea concentrations of 16 lactating women from a prospective clinical trial (HELPS, NCT02990598) were used for the development of the population PK model using nonlinear mixed effect modeling with NONMEM [3]. First-order conditional estimation with interaction (FOCE-I) was employed throughout to estimate the population PK parameters, the random effect of inter-individual variability, and residual variability. The plasma PK parameters were first estimated using plasma concentration data, then parameters describing milk compartment data were estimated with fixed plasma PK parameters. Results: A hydroxyurea plasma PK profile was described by a two-compartment model with first-order absorption and lag time. The breast milk PK data were described using a one-compartment model including volume of distribution of the milk compartment and inter-compartmental clearance between systemic plasma and milk compartments. Nonparametric bootstrap analysis confirmed the stability of parameter estimates. Visual predictive check (VPC) demonstrated that the simulated plasma and milk concentrations were in reasonable agreement with the observed data. Conclusion: A semi-mechanistic population PK model has been successfully developed to describe the hydroxyurea concentration-time profiles in plasma and breast milk in lactating women. The developed model can serve as a tool to simulate real-life lactation scenarios and predict hydroxyurea exposure through breastfeeding, allowing optimal drug administration and breastfeeding timing to minimize infant potential toxicity risk. Citations: [1] Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4: 18010.[2] Dong M, Ware RE, Dallmann A, Vinks AA. Hydroxyurea treatment for sickle cell anemia during pregnancy and lactation: Current evidence and knowledge gaps. Pharmacotherapy 2023; 43: 419-29.[3] Ware RE, Marahatta A, Ware JL, McElhinney K, Dong M, Vinks AA. Hydroxyurea Exposure in Lactation: a Pharmacokinetics Study (HELPS). J Pediatr 2020; 222: 236-9.