Hydroxyurea Pharmacokinetics in Children with Sickle Cell Anemia: Comparison of Global Cohorts

Introduction: Hydroxyurea treatment for children with sickle cell anemia (SCA) reduces pain, blood transfusions, stroke, and early mortality. Hydroxyurea dose escalation studies demonstrate the drug is most beneficial at the maximum tolerated dose (MTD), which is the dose that optimizes fetal hemoglobin induction without untoward myelotoxicity. There is wide interpatient variability in hydroxyurea MTD due to individual differences in pharmacokinetic (PK) parameters. Traditional MTD determination requires stepwise dose adjustments that take 6-12 months and are burdensome for patients and clinicians. We previously developed a hydroxyurea PK model from American children with SCA (HUSTLE, NCT00305175), which informed a PK dosing strategy that was prospectively demonstrated to improve outcomes without excess toxicity (TREAT, NCT02286154). However, the majority of children with SCA live in low-resource settings where the logistical burdens of dose titration are greater, and where upfront PK-guided dose determination could simplify and optimize dosing. Hydroxyurea PK parameters of children with SCA living in Africa and the Caribbean, who have different nutritional, environmental, and genetic influences, need to be analyzed and compared to American patients to ensure the PK model is appropriate to use in these populations.

Methods: After written informed consent, timed blood samples were collected from children with SCA enrolled on the NOHARM (Uganda, NCT03128515), REACH (Uganda and Kenya, NCT01966731), and EXTEND (Jamaica, NCT02556099) trials. Hydroxyurea concentrations were collected with sparse sampling and quantified via HPLC or mass spectrometry. PK dosing software (HdxSim) was used to determine each individual’s hydroxyurea absorption, volume of distribution, and clearance and to calculate the daily dose predicted to achieve MTD based on the target hydroxyurea exposure of 115 mg*h/L established from the HUSTLE cohort. One-way analysis of variance (ANOVA) testing was used to compare the PK parameters among geographic regions (USA, Africa, Caribbean).

Results: Hydroxyurea PK profiles were collected and analyzed from 425 children: 122 American, 262 African, and 42 Caribbean. There was variation in age (range 0.5-18 years), weight (7-88 kilograms), and hydroxyurea test dose (13-44 mg/kg) across regions based on the trial methods and eligibility. There were no differences in hydroxyurea absorption (p=0.40), volume of distribution (p=0.38), or clearance (p=0.24). The doses recommended to achieve MTD were not significantly different across global regions; the mean ± standard deviation (SD) in mg/kg/day was 28.3 ± 7.3 in the American cohorts, 29.5 ± 10.6 in the African cohorts, and 27.4 ± 11.2 in the Caribbean cohort (p=0.30, f=1.2). Of the 425 participants, 144 (34%; 63 American, 39 African, and 42 Caribbean) had PK profiles collected at MTD. There were no statistically significant differences in exposure; the mean ± SD in mg*hr/L was 115 ± 29 in the American cohort, 100 ± 40 in the African cohort, and 111 ± 46 in the Caribbean cohort (p=0.16, f=1.9).

Conclusion: Hydroxyurea PK parameters of children with SCA from around the world are consistent in absorption, volume of distribution, clearance, dose predicted to reach MTD, and hydroxyurea exposure at MTD. The PK model is robust despite variations in sampling technique, storage conditions, and chromatographic analysis across study methods. Future trials will evaluate the feasibility, safety, benefits, and cost effectiveness of prospective PK-guided hydroxyurea dosing in Africa and the Caribbean. PK-guided dosing may allow more children to be treated with hydroxyurea at MTD upfront, maximizing the benefits of this life-saving medication without stepwise escalation.