Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusions in Ugandan Children with Sickle Cell Anemia: Study Design of the Alternative Dosing And Prevention of Transfusions Trial

Abstract

Introduction: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda.

Methods: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments.

Conclusion: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa.

Introduction: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda.

Methods: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments.

Conclusion: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa.

Keywords: Hydroxyurea; Personalized medicine; Pharmacokinetics; Sickle cell anemia; Transfusion medicine.

Fig. 1.

ADAPT schema: After written informed consent, all participants will begin a screening period which may last up to 3 months during which they receive the local standard of care treatment for sickle cell anemia. During this period, all participants will undergo hydroxyurea pharmacokinetic testing, and those for whom a dose is fully generated that is within a standard dosing range will start on their individualized dose. Otherwise, participants will start on a default, weight-based dose per Ugandan national guidelines. All participants will be treated with hydroxyurea for 1 year with dose adjustments for weight gain or laboratories. The transfusion rate between the screening and treatment period is the primary endpoint for ADAPT. Secondary endpoints include an evaluation of the feasibility of pharmacokinetic-guided dosing.

Fig. 2.

Algorithm of transfusion indications: The indication for transfusion will be classified based on the following algorithm.

Fig. 3.

Novel tools to facilitate pharmacokinetic-guided dosing of hydroxyurea. a Portable high-performance liquid chromatography (HPLC, SmartLife) machine adapted to measure serum hydroxyurea concentrations. b Interface for user-friendly hydroxyurea PK software (HdxSim).

Fig. 4.

CONSORT diagram to track the feasibility of each step of proposed pharmacokinetic-guided hydroxyurea dosing process.