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Mathematical Modeling of Hydroxyurea Therapy in Individuals with Sickle Cell Disease
Pharmaceutics  (IF6.321),  Pub Date : 2022-05-16, DOI: 10.3390/pharmaceutics14051065
Akancha Pandey, Jeremie H. Estepp, Rubesh Raja, Guolian Kang, Doraiswami Ramkrishna

Sickle cell disease (SCD) is a chronic hemolytic anemia affecting millions worldwide with acute and chronic clinical manifestations and early mortality. While hydroxyurea (HU) and other treatment strategies managed to ameliorate disease severity, high inter-individual variability in clinical response and a lack of an ability to predict those variations need to be addressed to maximize the clinical efficacy of HU. We developed pharmacokinetics (PK) and pharmacodynamics (PD) models to study the dosing, efficacy, toxicity, and clinical response of HU treatment in more than eighty children with SCD. The clinical PK parameters were used to model the HU plasma concentration for a 24 h period, and the estimated daily average HU plasma concentration was used as an input to our PD models with approximately 1 to 9 years of data connecting drug exposure with drug response. We modeled the biomarkers mean cell volume and fetal hemoglobin to study treatment efficacy. For myelosuppression, we modeled red blood cells and absolute neutrophil count. Our models provided excellent fits for individuals with known or correctly inferred adherence. Our models can be used to determine the optimal dosing regimens and study the effect of non-adherence on HU-treated individuals.