Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia
Open accessAbstract
Hydroxyurea is FDA‐approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight‐based dosing with step‐wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single‐center study designed to prospectively validate a novel personalized PK‐guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9‐26 months), and PK‐guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3‐9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK‐guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK‐guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight‐based dosing.
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Hydroxyurea started at approximately 11 months at a dose of approximately 27 mg/kg was associated with HbF levels of 33.3±9.1%; 33% of patients had HbF greater than 40% with a hemoglobin concentration of 10.1±1.3 g/dL; acute events were markedly reduced; and toxicity was minimal.
“Hydroxyurea started at ;11 months at a dose of ;27 mg/kg was associated with HbF levels of 33.3 6 9.1%; 33% of patients had HbF .40% with a hemoglobin concentration of 10.1 6 1.3 g/dL; acute events were markedly reduced; and toxicity was minimal.89”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [89]
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- Authors
- McGann, P. T., Niss, O., Dong, M., Marahatta, A., Howard, T. A., Mizuno, T., Lane, A., Kalfa, T. A., Malik, P., Quinn, C. T., Ware, R. E., & Vinks, A. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- McGann, Patrick T.
- ORCID
- Venue
- American Journal of Hematology
- Publisher
- Wiley
- Published
- 2019-06-12
- Volume
- 94
- Issue
- 8
- Pages
- 871-879
- ISSN
- 0361-8609 (ISSN-L)
- 1096-8652
- PMC
- PMC6639795
- OpenAlex
- W2944852231
- Cited by
- 105
- References
- 41
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 4 · 2023: 40 · 2022: 8 · 2021: 13 · 2020: 21 · 2019: 3 · 2017: 1
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K23HL128885)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal Health and Biochemistry
- Keywords
- hydroxyurea, sickle cell disease, pediatric patients, pharmacokinetic-guided dosing, individualized dosing, maximum tolerated dose, hemoglobin, fetal hemoglobin, population pharmacokinetic model, weight-based dosing
- MeSH terms
- Adolescent, Anemia, Sickle Cell, Antisickling Agents, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Humans, Hydroxyurea, Infant, Male, Models, Biological, Prospective Studies, Drug Monitoring, Practice Guidelines as Topic, Area Under Curve, Maximum Tolerated Dose, Young Adult
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