Background: Hydroxyurea is a first-line pharmacotherapy for sickle cell anemia (SCA) with approved safety and efficacy. Previous studies have demonstrated that the clinical and laboratory benefits are optimized when the dose is escalated to maximum tolerated dose (MTD). However, there is significant inter-patient variability in MTD, and the trial-and-error dose escalation process is tedious requiring many blood draws and dose adjustments based on laboratory results. Even the most careful dose escalation approach takes at least 6-12 months to reach MTD. Over the past 8 years, our research team has developed and prospectively evaluated a novel individualized pharmacokinetics (PK)-guided hydroxyurea dosing strategy for pediatric patients with SCA to target a hydroxyurea exposure level, defined by the area under the concentration-time curve (AUC) associated with MTD. We reported a robust laboratory and clinical response using this individualized dosing strategy through the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154). TREAT participants had PK studies performed prior to initiation of hydroxyurea and upon reaching MTD. Aligning with the current treatment paradigm, the TREAT cohort was very young with most participants ≤2 years of age, representing a unique population much younger than those included in previous pediatric PK studies. The objective of the current analysis is to summarize the hydroxyurea PK in this very young cohort of children with SCA and compare these results to PK profiles from previous studies of older children.

Methods: PK data from 50 pediatric patients with SCA (median age 0.9 years, range 0.5-19.5 years) were included in the current analysis. Each participant received a 20 mg/kg dose of hydroxyurea, and hydroxyurea concentrations were measured approximately 15, 60, and 180 minutes following this dose. This sample collection schedule was determined using D-optimal design, based on previous hydroxyurea PK studies. Quantitative measurement of the hydroxyurea concentration was performed by high performance liquid chromatography (HPLC) or liquid chromatography with tandem mass spectroscopy (LC-MS/MS) requiring only small volumes of blood. Based upon these concentrations, informed by a population PK model, an individualized, PK-guided starting dose was calculated using Bayesian estimation with a clinical pharmacokinetic software MW/Pharm (Mediware, Prague, Czech Republic). In addition to these baseline results, repeat PK studies were also performed and available in a subset of patients (n=28) who had a second PK collection after MTD was achieved.

Results: Consistent with previous studies in adults and in older children, the hydroxyurea clearance exhibits large variability with a range of 5.9 to 23.5 L/h/70kg, supporting the need for individualized dosing in young children. For 50 subjects, the mean oral clearance was 12.1 ± 3.4 L/h, slightly lower than the hydroxyurea clearance of 12.7 L/h in older children who participated in the HUSTLE trial (median age 8.8 years), perhaps reflective of premature elimination function in young children with SCA.

There were 28 participants who had PK studies performed both at baseline and upon reaching MTD with an average time interval of 19.8 ± 9.4 months. The initial PK-guided dose recommendation was 31.7 ± 10.6 mg/kg and decreased to 25.3 ± 4.5 mg/kg at the MTD (∆ = -6.3 ± 9.5 mg/kg). At the second visit the average AUC was significantly higher than at baseline, increased from 79.5 ± 23.3 to 97.44 ± 33.57 mg*h/L. Although only 5/28 (18%) reached or surpassed the targeted AUC (115 mg*h/L), our modeling predicts that the projected AUC would have been 120 mg*h/L if the dose was regularly updated to account for interim weight gain to maintain the same mg/kg dosing.

Conclusion: In this robust analysis of hydroxyurea PK in young children with SCA, infants and young children have lower hydroxyurea clearance than older children and adults, suggesting a possible maturation in hydroxyurea clearance. Further studies with larger sample sizes will help to fully characterize the developmental changes of hydroxyurea PK in children. These PK data support our hypothesis that higher dosing is necessary in young children with subsequent dose adjustments to account for weight gain to maintain the level of hydroxyurea exposure required to optimize clinical benefits.

Ware:BMS: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.

Author notes

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Asterisk with author names denotes non-ASH members.

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