Hydroxyurea Pharmacokinetics and Precision Dosing in Sickle Cell Disease: A Scoping Review

Background: Hydroxyurea is the cornerstone disease-modifying therapy for sickle cell disease (SCD), but interindividual pharmacokinetic (PK) variability contributes to differences in drug exposure and treatment response. This scoping review synthesised evidence on hydroxyurea PK, pharmacodynamic (PD) relationships, determinants of exposure, pharmacometric modelling, and precision dosing approaches in SCD. Methods: A scoping review was conducted according to PRISMA-ScR guidance. Studies involving paediatric or adult patients with SCD that evaluated hydroxyurea PK, PK-PD relationships, exposure determinants, pharmacometric modelling, or PK-guided dosing were included. Study characteristics, PK parameters, covariates, modelling approaches, and key findings were charted and synthesised descriptively. Results: Twenty-seven studies published between 2005 and 2026 were included. Hydroxyurea demonstrated rapid oral absorption (Tmax 0.73–1.7 h), a short elimination half-life (1.7–2.9 h), and variability in systemic exposure across individuals (coefficient of variation approximately 40–45%). Body weight and renal function were the most consistently identified determinants of disposition, with renal impairment associated with reduced clearance and increased exposure. PK of hydroxyurea were well described by population PK and physiologically based PK models. PK-guided dosing showed potential to shorten the time to maximum tolerated dose and improve haematological responses. However, exposure–response and exposure–toxicity relationships remain insufficiently characterised, and evidence directly linking hydroxyurea exposure to patient-centred clinical outcomes was limited. Conclusions: Pharmacometric modelling and model-informed precision dosing (MIPD) have potential to support individualised hydroxyurea therapy, particularly in paediatric patients and those with altered renal function. Prospective external validation across diverse paediatric and adult populations, together with validated exposure–response and exposure–toxicity targets and clinically meaningful efficacy and safety outcomes, is required before routine clinical application can be recommended.