Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations

Abstract

Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), but has wide interpatient dosing variability due to pharmacokinetic (PK) differences. Whether hydroxyurea PK parameters differ among children with SCA in different global regions is unknown. We compared hydroxyurea PK parameters among children with SCA from five clinical trials: HUSTLE (USA, NCT00305175), TREAT (USA, NCT02286154), NOHARM (Uganda, NCT01976416), REACH (Uganda and Kenya, NCT01966731), and EXTEND (Jamaica, NCT02556099). Key hydroxyurea PK parameters were determined using HdxSim™, a validated hydroxyurea PK-software program. The results were compared across regions by one way analysis of variance. The influence of laboratory and clinical variables on PK-guided doses were evaluated by linear regression. PK profiles from 451 children with SCA were included: 146 from the USA, 265 from Africa, and 40 from the Caribbean. Children from Africa had slightly lower volumes of distribution (p<0.001), but absorption rate (p=0.07) and clearance (p=0.2) were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar: 26.6 ± 5.9, 27.6 ± 6.5, and 25.2 ± 4.7 mg/kg/day, respectively (p=0.04). In multivariable regression, younger age and increased reticulocyte counts were associated with higher PK-recommended doses. Hydroxyurea PK parameters in children with SCA differ minimally across global populations, predicting clinically similar doses to achieve MTD. Individualized hydroxyurea dosing based on a PK-population model derived from American children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations.