药代动力学指导下的羟基脲减少乌干达镰状细胞贫血儿童输血：替代给药与输血预防试验的研究设计
Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusions in Ugandan Children with Sickle Cell Anemia: Study Design of the Alternative Dosing And Prevention of Transfusions Trial.
作者信息
Power-Hays Alexandra, Namazzi Ruth, Kato Charles, McElhinney Kathryn E, Conroy Andrea L, Hume Heather, John Chandy, O'Hara Sara M, Stuber Susan E, Lane Adam, Latham Teresa S, Opoka Robert O, Ware Russell E
机构信息
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
出版信息
Acta Haematol. 2025;148(2):208-219. doi: 10.1159/000539541. Epub 2024 Jun 5.
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.
引言
镰状细胞贫血（SCA）患者可能需要频繁输血来治疗急慢性并发症。羟基脲是一种可挽救SCA患者生命的治疗方法，还可减少输血需求。药物获取不足以及剂量优化方面的挑战限制了羟基脲在非洲的广泛使用。如果可行，药代动力学（PK）给药可能会改善剂量确定，以将毒性降至最低并使临床益处最大化。替代给药与输血预防（ADAPT，NCT05662098）试验将分析羟基脲对输血率的影响，并作为一项试点研究来评估在乌干达进行PK引导的羟基脲给药的可行性。
方法
在此，我们描述了ADAPT的基本原理和设计，这是一项针对乌干达金贾约100名SCA儿童的前瞻性队列研究。主要假设是，与3个月预处理期和12个月治疗期之间的输血发病率比值相比，羟基脲将使输血使用率降低≥50%。一个关键的次要假设是，我们的PK给药方法将为≥80%的参与者生成合适的羟基脲剂量。每位ADAPT参与者都将接受羟基脲PK测试，如果生成的剂量在15 - 35毫克/千克/天之间，参与者将开始使用个体化剂量。如果未生成，则他们将开始使用20毫克/千克/天的默认剂量。羟基脲剂量将通过定期调整进行优化。
结论
总体而言，证明羟基脲治疗可降低输血利用率将有助于增加羟基脲的可及性，并且PK引导的羟基脲给药应能优化撒哈拉以南非洲地区SCA的安全有效治疗。
引言
镰状细胞贫血（SCA）患者可能需要频繁输血来治疗急慢性并发症。羟基脲是一种可挽救SCA患者生命的治疗方法，还可减少输血需求。药物获取不足以及剂量优化方面的挑战限制了羟基脲在非洲的广泛使用。如果可行，药代动力学（PK）给药可能会改善剂量确定，以将毒性降至最低并使临床益处最大化。替代给药与输血预防（ADAPT，NCT05662098）试验将分析羟基脲对输血率的影响，并作为一项试点研究来评估在乌干达进行PK引导的羟基脲给药的可行性。
方法
在此，我们描述了ADAPT的基本原理和设计，这是一项针对乌干达金贾约100名SCA儿童的前瞻性队列研究。主要假设是，与3个月预处理期和12个月治疗期之间的输血发病率比值相比，羟基脲将使输血使用率降低≥50%。一个关键的次要假设是，我们的PK给药方法将为≥80%的参与者生成合适的羟基脲剂量。每位ADAPT参与者都将接受羟基脲PK测试，如果生成的剂量在15 - 35毫克/千克/天之间，参与者将开始使用个体化剂量。如果未生成，则他们将开始使用20毫克/千克/天的默认剂量。羟基脲剂量将通过定期调整进行优化。
结论
总体而言，证明羟基脲治疗可降低输血利用率将有助于增加羟基脲的可及性，并且PK引导的羟基脲给药应能优化撒哈拉以南非洲地区SCA的安全有效治疗。
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