Pharmacokinetic and pharmacodynamic investigations. (A) Scatterplot of observed hydroxyurea plasma concentration vs time after the most recent dose. Circles represent quantified observations and triangles represent the Below Limit of Quantification (BLQ) observations positioned at half the lower limit of quantitation. Black shapes depict observations included in the final population PK model development, whereas blue shapes depict BLQ observations that were excluded owing to model instability. The data are plotted using a log₁₀ Y-axis scale. (B) Boxplot of simulated hydroxyurea C_max (C) and AUC_(0-inf) after 8 weeks of 15 mg/kg per day stratified by age group. Box-and-whisker plots are stratified by age group. Each box covers the IQR, with the median as the vertical black line inside the box, and with the whiskers extending to the last data point within 1.5 times the IQR. A total of 1000 virtual patients were simulated for each age group. Blue circles depict the simulated values within each age group. (D) Mean %HbF over the course of the study. Error bars represent the standard error of the mean. (E) Individual subject changes in %HbF from baseline to the end of the study stratified by age group. The red dotted line represents the 20% target threshold associated with improved clinical outcomes.⁶ IQR, interquartile range.