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.