Physiologically based pharmacokinetic modeling of hydroxyurea: Implications for dose adjustment in patients with...

Hydroxyurea is widely used in the management of sickle cell anemia. However, its pharmacokinetics can be significantly altered in patients with renal impairment, which is a common complication affecting approximately 30 % of patients with sickle cell anemia. These alterations can have an impact on drug efficacy and safety, necessitating individualized dosing strategies. PBPK models of hydroxyurea in GastroPlus were used to predict the disposition of the drug in adults with normal and impaired renal function by incorporating normal and disease-specific physiology. Simulated pharmacokinetic parameters for hydroxyurea, including C_max, AUC, and T_max, showed agreement with observed clinical data for patients with normal renal function (fold errors 0.8-1.2). The model was further validated in patients with hyperfiltration and renal dysfunction. Further simulations indicated that dose reductions of about 10 %, 25 % and 45 % are required to give the clinical target AUC in patients with mild, moderate and severe renal impairment, respectively, for patients of weight 40 to 80 kg. These results show that the PBPK model of hydroxyurea is useful for optimizing dosing in adults with sickle cell anemia to enable safer, individualized therapy.