Hydroxyurea pharmacokinetics, it is a small world after all

In this issue of Blood Advances, Power-Hays et al¹ provide strong evidence that the pharmacokinetic (PK) recommended dose of hydroxyurea to achieve maximum tolerated dose (MTD) can be applied globally.

Hydroxyurea treatment remains the standard of care for both children and adults with sickle cell anemia (SCA), with the World Health Organization including it on its Essential Medicines List.² Hydroxyurea provides benefit by increasing fetal hemoglobin (HbF), improving red blood cell rheology, and reducing vasculopathy and inflammation.³ Various dosing regimens are used worldwide, including fixed low dose, 10 mg/kg per day; moderate dose, 20 mg/kg per day, or dose escalation to MTD, in which an individualized dose that maximizes HbF induction while minimizing toxicity is chosen. In the United States the latter regimen is utilized, because it has been associated with improved clinical outcomes over fixed dosing including increased Hb and decreased hospitalizations, blood transfusions, and risk of stroke.⁴ Despite this, some studies in low- to middle-income countries (LMICs) have shown good success with low or moderate doses of hydroxyurea, with strong safety, efficacy, and clinical outcomes including a reduction in stroke rates and transcranial doppler velocities.^5,6 There is variability in hydroxyurea MTD and there are so called hydroxyurea “non-responders.”⁷ However, this could be due to PK parameters including absorption, distribution, and clearance. No one has compared different global cohorts to determine how much variation exists worldwide. If individualized PK parameters could be applied, decreasing time to achieving MTD, improved clinical outcomes could be achieved.

The authors set out to determine the degree of variation in these PK parameters across 5 previously studied global cohorts. They analyzed PK profiles across 5 hydroxyurea clinical trials including 2 studies with 146 children in the United States (HUSTLE and TREAT), 2 studies with 265 children in Africa (NOHARM in Uganda and REACH in Kenya), and 1 study with 40 children in the Caribbean (EXTEND, Jamaica). The ages ranged from 0.5 to 19.5 years with a median of 6.8 years. Children were older in the Caribbean study secondary to clinical trial methods and eligibility. Children in the United States studies were less underweight with lower baseline creatinine values than the other groups. Similar PK parameters were observed across the studies, with no significant differences in absorption rates or hydroxyurea clearance. Despite a statistically significant difference in the PK-recommended dose to achieve target hydroxyurea MTD (26.6 mg/kg in the United States, 27.6 mg/kg in Africa, and 25.2 mg/kg in the Caribbean cohort), it would be unlikely that these doses pose a clinical difference. The PK-recommended dose showed a negative correlation with age, creatinine, and absolute neutrophil count, whereas a positive correlation was shown with HbF and absolute reticulocyte count. Importantly, these doses did not lead to any significant neutropenia, which is reassuring given the fact that there could be a higher incidence of Duffy-null neutropenia, especially in Africa or the Caribbean. Older children need a lower dose of hydroxyurea than younger children. For every 10-year increment in age, a 0.5 mg/kg per day decrease in the recommended hydroxyurea dose is observed. Despite differences in environment, age, laboratory parameters, body composition, PK sampling and analysis methods, similar hydroxyurea PK parameters are observed across these global cohorts.

This work is the first to compare hydroxyurea PK parameters and PK-recommended dosing across different geographic regions, including cohorts from the United States, Uganda, Kenya, and Jamaica. It shows that clinically similar PK dosing, ranging from 25 to 27 mg/kg per day, can be applied globally despite differences in genetics, body composition, and environmental factors. These findings support the fact that a starting dose of 25 mg/kg per day can be tolerated by most children in areas other than the United States. This is very reassuring given the bulk of sickle cell disease is not in the United States. A hydroxyurea dose around 25 mg/kg per day is safe and effective not only in the United States but also in regions of Africa and the Caribbean.

There is no need to suggest that low dose hydroxyurea is safer in LMICs due to their inability to have frequent laboratory monitoring as significant myelosuppression at PK-recommended dosing was not seen and importantly was shown to be tolerated in regions where malaria is endemic. There is a need for further PK-recommended dosing studies across other geographic locations, including different regions in Africa, South America, and India. Power-Hays et al study highlights not only the safety and tolerability of hydroxyurea across different geographic regions but also the importance of offering appropriate doses to allow children with SCA globally to experience the maximal benefit.

Conflict-of-interest disclosure: A.A.-K. received research support from Novo Nordisk, New York; served on the advisory board of Chiesi; and provided consultancy for Federal Public Defender. C.C. declares no competing financial interests.