PII-034 - THE FEASIBILITY OF PHARMACOKINETIC-GUIDED HYDROXYUREA DOSING FOR CHILDREN WITH SICKLE CELL ANEMIA IN UGANDA: ANALYSIS OF THE ALTERNATIVE DOSING AND PREVENTION OF TRANSFUSIONS (ADAPT) TRIAL.

A. Power-Hays^1,2, R. Namazzi³, C. Kazinga⁴, I. Mufumba⁴, T. Latham⁵, A. Conroy⁴, R. Opoka³, A. Vinks⁶, M. Dong⁶, R. Ware^1,2; ¹Cincinnati Children's Hospital, Division of Hematology, Cincinnati, OH, USA, ²University of Cincinnati, Cincinnati, OH, USA, ³Makerere University, ⁴Global Health Uganda, ⁵Cincinnati Children's Hospital Medical Center, ⁶Cincinnati Children's Hospital, Division of Clinical Pharmacology.

Background: Hydroxyurea is the primary treatment of sickle cell anemia (SCA), but dose optimization can be time-consuming and resource-intensive, posing a particular challenge in Africa where over 75% of people with SCA live. Pharmacokinetic (PK)-guided dosing based on target drug exposure improves clinical outcomes without increased toxicity. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial is a pilot study evaluating the feasibility of determining a PK-guided hydroxyurea dose in Uganda to treat children with SCA.

Methods: ADAPT is a prospective cohort study of children 1-10 years old with SCA in Uganda. All participants completed PK testing with optimal sparse sampling (30, 60, & 180 min) after a 500 mg oral hydroxyurea test dose. Serum hydroxyurea concentrations were determined via chemical derivatization and portable HPLC. HdxSim, a model-informed precision dosing program using Bayesian estimation and a population PK model, was used to determine AUC and calculate the dose needed to achieve target exposure of 115 mg*hr/L. We determined the proportions of participants for whom 1) our full process was completed and 2) the PK-recommended dose was within 15-35 mg/kg/day based on American SCA trials.

Results: Of 106 participants enrolled, all completed PK collection. Hydroxyurea concentrations were determined via HPLC for 86 (81%) participants, and a PK-guided starting dose was determined for 85 (80%). The mean test dose was 33.1 ± 10.6 mg/kg and AUC achieved was 100.0 ± 55.7 mg*hr/L. The mean PK-recommended dose was 40.3 ± 12.4 mg/kg/day. PK-recommended doses for 32 (30%) of participants were within the specified 15-35 mg/kg/day range.

Conclusion: This pilot feasibility study demonstrates that PK-guided dosing is acceptable and feasible with optimal sparse sampling, our portable HPLC, and HdxSim software. Challenges in the current process include sample transport and a complex colorimetric assay; both might allow hydroxyurea degradation, resulting in a lower than expected AUC and higher PK recommended dose. More evaluation of sample quality is needed before comparing PK parameters between Ugandan and American children with SCA. Based on the ADAPT trial, an upcoming multi-national trial using PK-guided hydroxyurea dosing will reduce sample transport and utilize a simplified hydroxyurea chemical assay.