Stroke Prevention with Hydroxyurea Enabled through Research and Education: A Phase 2 Primary Stroke Prevention Trial in Sub-Saharan Africa

Smart, Luke R.; Ambrose, Emmanuela E.; Balyorugulu, Georgina; Songoro, Primrose; Shabani, Idd; Komba, Protas; Charles, Mwesige; Howard, Thad A.; McElhinney, Kathryn E.; O’Hara, Sara M.; Odame, Jodie; Nakafeero, Maria; Adams, Janet S.; Stuber, Susan E.; Lane, Adam; Latham, Teresa; Makubi, Abel; Ware, Russell E.

doi:10.1159/000526322

Cited by 5 publications

(3 citation statements)

References 48 publications

(55 reference statements)

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“…We are also testing a separate hydroxyurea assay that requires less chemical manipulation and shortens the time of preparation and evaluation of specimens so that PK-guided dosing could more easily be accomplished in a busy clinical laboratory. We will be testing PK-guided precision dosing in two upcoming clinical trials in Tanzania (SPHERE, NCT 03948867) and Uganda (ADAPT, NCT 05662098) ( Smart et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings

Smart

Charles

McElhinney

et al. 2023

Front. Mol. Biosci.

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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.

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Section: Discussionmentioning

confidence: 99%

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings

Smart

Charles

McElhinney

et al. 2023

Front. Mol. Biosci.

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“… 72 , 73 An ongoing clinical trial is evaluating the up-front use of hydroxyurea for primary stroke prophylaxis in regions without access to chronic transfusion. 74 …”

Section: Primary Stroke Preventionmentioning

confidence: 99%

Managing the Cerebrovascular Complications of Sickle Cell Disease: Current Perspectives

Light¹,

Boucher²,

Baskin‐Miller³

et al. 2023

JBM

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The importance of protecting brain function for people with sickle cell disease (SCD) cannot be overstated. SCD is associated with multiple cerebrovascular complications that threaten neurocognitive function and life. Without screening and preventive management, 11% of children at 24% of adults with SCD have ischemic or hemorrhagic strokes. Stroke screening in children with SCD is well-established using transcranial Doppler ultrasound (TCD). TCD velocities above 200 cm/s significantly increase the risk of stroke, which can be prevented using chronic red blood cell (RBC) transfusion. RBC transfusion is also the cornerstone of acute stroke management and secondary stroke prevention. Chronic transfusion requires long-term management of complications like iron overload. Hydroxyurea can replace chronic transfusions for primary stroke prevention in a select group of patients or in populations where chronic transfusions are not feasible. Silent cerebral infarction (SCI) is even more common than stroke, affecting 39% of children and more than 50% of adults with SCD; management of SCI is individualized and includes careful neurocognitive evaluation. Hematopoietic stem cell transplant prevents cerebrovascular complications, despite the short- and long-term risks. Newer disease-modifying agents like voxelotor and crizanlizumab, as well as gene therapy, may treat cerebrovascular complications, but these approaches are investigational.

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“…Reduction in inflammatory markers (white blood cell count, platelet count) Brain Improved neurocognitive function 22,23 Reduced transcranial Doppler (TCD) velocities 24,25 Reduction in stroke and stroke risk 26,27 Heart Reduction in myocardial fibrosis 28 Reverse cardiac remodeling and improvement in cardiomyopathy 29 Lungs Improved pulmonary hypertension 30 Reduced acute chest syndrome 11,19,31 Kidneys Improved urinary concentrating ability and less renal enlargement 32 Reduced proteinuria 33 Immune system Reduction in malaria for children in Africa 34 Improved splenic function 17 Mortality Reduced mortality for adults in the MSH Study (US) 14 Reduced mortality for children in Brazil 35 Reduced mortality for children in Belguim 36 Reduced mortality for children in sub-Saharan Africa…”

Section: Increased Hemoglobinmentioning

confidence: 99%

Hydroxyurea for children with sickle cell disease in sub‐Saharan Africa: A summary of the evidence, opportunities, and challenges

Dexter

McGann

2023

Pharmacotherapy

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Sickle cell disease (SCD) is a common and life‐threatening inherited blood disorder that affects more than 300,000 newborns per year. Because of the origins of the sickle gene mutation as a protective mechanism against malaria for those with sickle cell trait, more than 90% of annual SCD births are in sub‐Saharan Africa (sSA). Over the past several decades, there have been many important advances in the care of individuals with SCD, including early diagnosis through newborn screening programs (NBS), prophylactic penicillin, the development of vaccines to prevent invasive bacterial infections, and the emergence of hydroxyurea as the primary disease‐modifying pharmacologic therapy. These relatively simple and inexpensive interventions have significantly reduced the morbidity and mortality of sickle cell anemia (SCA) such that individuals with SCD can live longer and more complete lives. Unfortunately, although these interventions are relatively inexpensive and evidence‐based, they are only readily available for affected individuals living in high‐income settings, representing <5% of the global SCD population. In sSA, where >90% of the global SCD burden exists, SCD still results in early mortality with 50–90% of infants likely dying before reaching 5 years of age. Recently, there are an increasing number of efforts in many African countries to prioritize SCA with pilot NBS programs, improved diagnostics, and expanded SCD education for health care professionals and the general public. It is essential to include access to hydroxyurea as a core component of any SCD care program, but there are still many barriers that prevent the widespread global use of hydroxyurea. Here, we summarize what we know about SCD and hydroxyurea use in Africa and discuss a strategy to respond to what we consider to be a public health imperative to maximize access to and appropriate use of hydroxyurea for all individuals with SCD using innovative dosing and monitoring strategies.

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Stroke Prevention with Hydroxyurea Enabled through Research and Education: A Phase 2 Primary Stroke Prevention Trial in Sub-Saharan Africa

Cited by 5 publications

References 48 publications

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings

Hydroxyurea pharmacokinetics and precision dosing in low-resource settings

Managing the Cerebrovascular Complications of Sickle Cell Disease: Current Perspectives

Hydroxyurea for children with sickle cell disease in sub‐Saharan Africa: A summary of the evidence, opportunities, and challenges

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