The Hydroxyurea Absorption Phenotype: A Key PK/PD Determinant in Sickle Cell Disease Treatment

Background/Objectives: Hydroxyurea (HU), a cornerstone treatment for sickle cell disease (SCD), exhibits marked interindividual pharmacokinetic/pharmacodynamic (PK/PD) variability that remains poorly understood. This study aimed to establish a population PK model using OPTIMDREP randomized trial data (NCT06464458), quantify parameter variability, and identify covariates influencing HU PK and hematological response. Methods: Plasma sampling data from 22 SCD patients (20 pediatric and 2 adult patients; median age: 11.2 years [range: 2.5–35.7]) on once-daily oral HU underwent a non-compartmental analysis (NCA) followed by nonlinear mixed-effects modeling (MonolixSuite®). PK variability covariates and PK/PD correlations with the mean corpuscular volume (MCV), reticulocytes, fetal hemoglobin percentage (HbF%) and neutrophils were investigated. Results: NCA identified two absorption phenotypes (rapid/slow), with higher maximum concentration values observed for rapid (36.5 ± 18.8 mg/L) compared to slow (22.3 ± 8.4 mg/L) (p = 0.0013) profiles but not statistically different total exposures, apparent clearances (Cl/F) or volumes of distribution (Vd/F). The population approach identified the one-compartment model (first-order absorption and linear elimination) and confirmed the absorption phenotype as the key absorption rate (ka) covariate (9.93 vs. 1.36 h−1), explaining half of the ka interindividual variability (IIV). The median-normalized body weight was retained for both the Cl/F and Vd/F, as it significantly reduced the objective function value. No hematological parameter was correlated to PK parameters. However, rapid absorbers showed a superior response on the MCV (Δ = 9.1 fL, p < 0.0001), reticulocytes (Δ = −42.2 G/L, p < 0.01), and HbF% trend (Δ = 2.8%, p = 0.0835) but not on neutrophil counts (p = 0.8757). Conclusions: The absorption phenotype, a novel covariate explaining half of the ka IIV, predicts a superior erythropoietic response without toxicity in SCD patients. These findings support absorption phenotype integration into PK-guided dosing algorithms to optimize early-response biomarkers and personalize HU therapy.