Hydroxyurea pharmacokinetics in children with sickle cell anemia across different global populations
Year: 2025
Type: article
Abstract: ABSTRACT: Hydroxyurea provides effective disease-modifying treatment for people with sickle cell anemia (SCA), especially when escalated to maximum tolerated dose (MTD), which 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 5 clinical trials: HUSTLE (United States), TREAT (United States), NOHARM (Uganda), REACH (Uganda and Kenya), and EXTEND (Jamaica). Key hydroxyurea PK parameters were determined using HdxSim, a validated hydroxyurea PK software program. The results were compared across regions by analysis of variance. PK profiles from 451 children with SCA (146 from the United States, 265 from Africa, and 40 from the Caribbean) were included. Children from Africa had slightly lower volumes of distribution, but absorption rate and clearance were similar across regions. The PK-recommended doses to achieve MTD were statistically different but clinically similar across the United States (26.6 ± 5.9 mg/kg per day), Africa (27.6 ± 6.5 mg/kg per day), and the Caribbean (25.2 ± 4.7 mg/kg per day) (P = .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 US children with SCA can be used broadly to maximize the benefits of this critical medication in other global populations. These trials were registered at www.ClinicalTrials.gov as #NCT00305175 (HUSTLE), #NCT02286154 (TREAT), #NCT01976416 (NOHARM), #NCT01966731 (REACH), and #NCT02556099 (EXTEND).
Source: Blood Advances
Authors: Alexandra Power-Hays, Kathryn E. McElhinney, Thomas N. Williams, George Mochamah, Peter Olupot-Olupot, George Paasi, Marvin E. Reid, Angela E. Rankine-Mullings, Robert O. Opoka, Chandy C. John, Patrick T. McGann, Charles T. Quinn, Nieko C. Punt, Luke R. Smart, Susan E. Stuber, Teresa S. Latham, Alexander A. Vinks, Russell E. Ware
Institutions: Cincinnati Children's Hospital Medical Center, University of Cincinnati, Kenya Medical Research Institute, KEMRI-Wellcome Trust Research Programme, Imperial College London, Mbale Hospital, Busitema University, University of the West Indies System, University of the West Indies, Aga Khan University Nairobi, Indiana University Indianapolis, Indiana University School of Medicine, Brown University, Rhode Island Hospital, Hasbro Children's Hospital, University Medical Center Groningen
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Awards: Therapeutic Response Evaluation and Adherence Trial: A Prospective Study of Hydroxyurea for Children with Sickle Cell Anemia, Realizing Effectiveness Across Continents with Hydroxyurea(REACH): A Phase I/II Pilot Study of Hyroxyurea for Children with Sickle Cell Anemia, Sickle Cell Anemia, Splenic Pathology, and Hydroxyurea in Sub-Saharan Africa, The Cleveland Clinic Innovation Accelerator, Hydroxyurea Pharmacokinetics and Pharmacogenomics, T32 Cincinnati Pediatric Clinical Pharmacology Training Program, Child Health Research Career Development Award (K1-Renewal Yrs 31-35)
OpenAlex ID: W4414642612