Efficacy, safety, and pharmacokinetics of a new, ready-to-use, liquid hydroxyurea in children with sickle cell anemia.

Despite the demonstrated efficacy and safety of liquid hydroxyurea for treating sickle cell anemia in children,1-3 the lack of a licensed liquid formulation presents challenges for patients, caregivers, and health care professionals. Treatment algorithms recommend early initiation of treatment and titrating weight-adjusted doses toward the maximum tolerated dose (MTD) with mild myelosuppression. With only capsule and tablet formulations of hydroxyurea approved globally, doses may need to be varied daily and rounded up or down. In some centers, to facilitate dose individualization and improve palat-ability, children are provided unlicensed liquid formulations compounded in pharmacies. Although such formulations meet a clinical need, they potentially expose children to medication errors, further compliance challenges due to unpalatability, and the consequential higher risk of adverse reactions or inadequate efficacy due to quality issues. For many patients, there are also significant challenges in accessing the compounded liquid hydroxyurea.4,5 A new, child-friendly, multidose, ready-to-use (no requirement for reconstitution) 100 mg/mL strawberry -flavored oral solution with a stable 2-year shelf life has been developed for licensing. This study aimed to determine population pharmacokinetics, safety, and efficacy in infants and older children with sickle cell anemia (SCA) (NCT03763656). This multicenter, open-label, prospective study was conducted in accordance with the principles of the International Conference on Harmonization-Good Clinical Practice guidelines and was approved by the UK Medicines Healthcare products and Regulatory Agency and the Ministry of Health and Wellness in Jamaica. Ethical approval was obtained from the North West Liverpool Central Research Ethics Committee, United Kingdom and the Mona Campus Research Ethics Committee, Kingston, Jamaica. This study was conducted in accordance with the principles of the Declaration of Helsinki. All children between 6 months and 18 years of age with sickle cell anemia (HbSS or HbS/& beta;0), who were previously hydroxyurea naive, were eligible for recruitment. The exclusion criteria included renal or hepatic insufficiency. All study participants started liquid hydroxyurea at 15 mg/kg once daily, with dose escalation every 8 to 12 weeks until MTD was achieved (absolute neutrophil count 1x 109/L to 3 x 109/L or a maximum dose of 35 mg/kg per day). The treatment was continued for 12 to 15 months. Venous blood samples for pharmacokinetics were collected on day 1 and at 6 months with additional single samples at interim clinical visits. Pharmacokinetic analysis using the modeling/simulation meth-odology is detailed in the supplemental File. Full blood counts, fetal hemoglobin (HbF), safety, and review of clinical symptoms were assessed throughout the study. In addition, an exploratory transcranial Doppler (TCD) assessment was performed at screening and at the end of the study.