Rationale, development, and validation of HdxSim, a clinical decision support tool for model-informed precision dosing (MIPD) of hydroxyurea for children with sickle cell anemia.

Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life-saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time-consuming, especially in low-income countries where most people with SCA live. Model-informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial-and-error dose adjustments. HdxSim, a user-friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real-world pharmacokinetic (PK) data. First-dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (HUSTLE, NCT00305175 and TREAT, NCT02286154). Areas under the concentration-time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm-DOS). The doses predicted by HdxSim and MWPharm-DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with <20% variance. The average (mean±SD) AUC for TREAT participants estimated with HdxSim (68.6±18.0 mg*hr/L) was lower than MWPharm-DOS (78.6±20.7 mg*hr/L, p=0.012), but the average recommended doses were not different (425 vs 423 mg/day, p=0.97). Moreover, HdxSim was non-inferior to MWPharm-DOS at predicting clinical MTD (absolute difference 3.9±5.8 vs 4.9±8.2 mg/kg/day, p=0.19). HdxSim accurately estimates hydroxyurea exposure and is non-inferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK-guided hydroxyurea dosing more accessible to this neglected population globally.