Assessment of pharmacokinetic profiles of hydroxyurea in children with sickle cell disease at sickle cell clinic, Mulago national referral hospital

Abstract

Background: Hydroxyurea (HU), initially developed as an anticancer agent, has become a cornerstone in the management of sickle cell disease due to its ability to induce fetal hemoglobin (HbF), reduce red blood cell sickling and adhesion, and improve clinical outcomes. At the Mulago Sickle Cell Clinic, HU is widely used in both pediatric and adult patients with promising results; however, there remains a lack of pharmacokinetic (PK) data on its use across varying doses and schedules in children aged 0–12 years. Understanding HU’s PK profile in this population is crucial for optimizing individualized dosing, enhancing efficacy, and minimizing toxicity. This information is vital for guiding clinical decisions and shaping policy, especially in resource-limited settings. Objective: To assess the effects of varying dosing schedules of hydroxyurea on the steady state plasma concentration of hydroxyurea in children aged 0-12 years with sickle cell anemia attending Mulago Sickle Cell Clinic. Methods: A pharmacokinetic study was conducted on 66 children on HU regimen. Informed consent was obtained from the caregivers of participating children using a structured questionnaire. Participants were recruited for the study, and 3 mL of blood samples were collected from veins in the antecubital fossa (inner elbow area). Plasma from each sample were analyzed for drug levels using liquid chromatography-mass–mass spectrometry (LC-MS). The resulting concentration-time data were used to estimate pharmacokinetic parameters through non-compartmental data analysis. Results: A total of 66 children participated in the study, each receiving an oral dose of hydroxyurea and providing three blood samples for pharmacokinetic analysis. The majority of participants were male and of primary school age. Children were grouped based on standard and alternate dosing schedules, with a slight difference in average body weight between the groups. Analysis of plasma concentrations showed that both dosing regimens resulted in comparable drug exposure, as assessed by the area under the concentration-time curve (AUC), indicating similar pharmacokinetic profiles between the two groups. Conclusion: This study examined pharmacokinetic variability of hydroxyurea in children with sickle cell disease on standard versus alternate dosing. Key parameters (AUC, Cmax, Cmin, and Tmax) showed no significant differences, indicating comparable systemic exposure between regimens. Variability in absorption, particularly Tmax, highlighted interindividual differences. Both dosing strategies achieved therapeutic AUC levels, supporting their clinical effectiveness. These results underscore the value of individualized dosing and pharmacokinetic monitoring in pediatric sickle cell treatment.