PWIV-003 - DEVELOPMENTAL CHANGES OF HYDROXYUREA PHARMACOKINETICS IN CHILDREN WITH SICKLE CELL ANEMIA.

M. Dong¹, T. Mizuno¹, A. Good², A. Hosawi¹, A. Vinks^1,3, R. Ware¹, P. McGann⁴; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²The Summit Country Day School, Cincinnati, OH, USA, ³University of Cincinnati, Cincinnati, OH, USA, ⁴Rhode Island Hospital, Providence, RI, USA.

Background: Hydroxyurea is a first-line pharmacotherapy for sickle cell anemia (SCA). Our team developed a pharmacokinetic (PK)-guided individualized dosing strategy for hydroxyurea and reported a robust laboratory and clinical response in the TREAT trial (NCT02286154). The TREAT cohort was very young with most participants ≤2 years of age. The objective of the current analysis is to summarize hydroxyurea PK profiles in this young cohort and compare to those from older children with SCA.

Methods: PK data from 50 patients with SCA in the TREAT study were available (median age: 0.9 years, range 0.5-19.5 years). Each participant received a 20 mg/kg dose of hydroxyurea, after which plasma concentrations were measured at approximately 15, 60, and 180 minutes, a sparse sampling schedule determined using D-optimal design. Individual PK parameters were estimated with MW/Pharm (Mediware, Prague, Czech Republic) based on a previously developed population PK model and using Bayesian estimation (1). PK results from the HUSTLE study (NCT00305175; n = 96; median age 8.8 years, range 1.2-16.6 years) were included for comparison (2).

Results: Consistent with previous studies in adults and older children, the hydroxyurea clearance exhibited large variability with a range of 5.9 to 23.5 L/h/70kg in the TREAT study, supporting the need for individualized dosing in young children. In patients 2 years and younger (n= 38), the mean oral clearance was 11.6 ± 3.1 L/h/70kg, which is significantly lower than 13.0 ± 2.4 L/h/70kg in children older than 2 years (n = 108 ; P = 0.012).

Conclusion: Infants and young children have lower hydroxyurea clearance than older children, likely reflective of maturation of clearance . Further studies with larger sample sizes will help to fully characterize the developmental trajectory of hydroxyurea PK.

1. Dong, M., McGann, P. T., Mizuno, T., Ware, R. E. & Vinks, A. A. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Br J Clin Pharmacol 81, 742-752.

2. Ware, R. E. et al. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118, 4985-4991.