Hydroxyurea pharmacokinetics and precision dosing in low-resource settings

Frontiers in Molecular Biosciences

Molecular Biosciences

Mwesige Charles¹  Emmanuela E. Ambrose²  Alexander A. Vinks³  Min Dong³  Kathryn E. McElhinney⁴  Thad Howard⁴  Russell E. Ware⁵  Luke R. Smart⁵  Alexandra Power-Hays⁵ 

[1] Department of Laboratory Sciences, Bugando Medical Centre, Mwanza, Tanzania;Department of Paediatrics and Child Health, Catholic University of Health and Allied Sciences, Mwanza, Tanzania;Department of Paediatrics and Child Health Bugando Medical Centre, Mwanza, Tanzania;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States;Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States;Global Health Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States;

关键词: sickle cell disease;    hydroxyurea;    pharmacokinetics;    precision dosing;    high performance liquid chromatography;   

DOI  :  10.3389/fmolb.2023.1130206

 received in 2022-12-22, accepted in 2023-05-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Hydroxyurea is effective disease-modifying treatment for sickle cell anemia (SCA). Escalation to maximum tolerated dose (MTD) achieves superior benefits without additional toxicities, but requires dose adjustments with serial monitoring. Pharmacokinetic (PK)-guided dosing can predict a personalized optimal dose, which approximates MTD and requires fewer clinical visits, laboratory assessments, and dose adjustments. However, PK-guided dosing requires complex analytical techniques unavailable in low-resource settings. Simplified hydroxyurea PK analysis could optimize dosing and increase access to treatment.Methods: Concentrated stock solutions of reagents for chemical detection of serum hydroxyurea using HPLC were prepared and stored at −80C. On the day of analysis, hydroxyurea was serially diluted in human serum, then spiked with N-methylurea as an internal standard and analyzed using two commercial HPLC machines: 1) standard benchtop Agilent with 449 nm detector and 5 micron C18 column; and 2) portable PolyLC with 415 nm detector and 3.5 micron C18 column. After validation in the United States, the portable HPLC and chemicals were transported to Tanzania.Results: A calibration curve using hydroxyurea 2-fold dilutions ranging from 0 to 1000 µM was plotted against the hydroxyurea:N-methylurea ratio. In the United States, both HPLC systems yielded calibration curves with R2 > 0.99. Hydroxyurea prepared at known concentrations confirmed accuracy and precision within 10%–20% of the actual values. Both HPLC systems measured hydroxyurea with <10% variance from the prepared concentrations, and paired analysis of samples on both machines documented <15% variance. Serial measurements of 300 and 100 μM concentrations using the PolyLC system were precise with 2.5% coefficient of variance. After transport to Tanzania with setup and training, the modified PolyLC HPLC system produced similar calibration curves with R2 > 0.99.Conclusion: Increasing access to hydroxyurea for people with SCA requires an approach that eases financial and logistical barriers while optimizing safety and benefits, especially in low-resource settings. We successfully modified a portable HPLC instrument to quantify hydroxyurea, validated its precision and accuracy, and confirmed capacity building and knowledge transfer to Tanzania. HPLC measurement of serum hydroxyurea is now feasible in low-resource settings using available laboratory infrastructure. PK-guided dosing of hydroxyurea will be tested prospectively to achieve optimal treatment responses.

【 授权许可】

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Copyright © 2023 Smart, Charles, McElhinney, Dong, Power-Hays, Howard, Vinks, Ambrose and Ware.