Distinct Phenotypes of Hydroxyurea Absorption among Children with Sickle Cell Anemia
Authors: Ware Russell E. , He Jin , Mortier Nicole A. , Howard Thad A. , Cheng Cheng , Flanagan Jonathan M. , Sparreboom Alex 
Published: October 2019

Abstract
Hydroxyurea therapy is now used commonly for both adults and children with sickle cell anemia (SCA), and has both laboratory and clinical efficacy. At doses ranging from 10–35 mg/kg/day, biologically important laboratory responses to hydroxyurea include induction of fetal hemoglobin (HbF), increased hemoglobin concentration, decreased circulating white blood cell and reticulocyte counts, and reduction of hemolysis (lower LDH). Treatment with hydroxyurea at the maximum tolerated dose (MTD) provides optimal laboratory responses in children with SCA. Despite the proven efficacy of this therapeutic option, hydroxyurea has a variable effect among patients with SCA that is not well understood. Patients have variability in their HbF and LDH responses, but also in the toxicity profile, which typically manifests as myelosuppression and limits the MTD. To understand better the variation in hydroxyurea responses and toxicities, we performed first-dose pharmacokinetic (PK) studies on a cohort of children with SCA who were initiating hydroxyurea therapy for clinical indications. As part of the prospective IRB-approved research protocol Hydroxyurea Study of Long-term Effects (HUSTLE, ClinTrials.gov NCT00305175), 40 pediatric patients received a single 20 mg/kg oral dose of hydroxyurea (range 18.0–21.6 mg/kg) and had timed venous blood collection at 0, 30, 60, 120, 240, and 480 minutes. Serum was assayed for hydroxyurea concentration using a colorimetric chemical assay. Estimates of PK parameters for hydroxyurea were derived from individual concentration-time data sets using model independent methods. Maximum plasma concentration (Cmax) and the time of maximum concentration (Tmax) were observed; area under the concentration-time curve (AUC) was calculated using the final quantifiable sample and also by extrapolation to infinity. Additional PK parameters included terminal half-life (t1/2), apparent volume of distribution (V/F), and apparent oral clearance (CL/F). For all 40 patients, the apparent oral clearance (CL/F) of hydroxyurea was 0.252 ± 0.080 L/hr/kg, which is slightly increased compared to previously published values for adults. Hydroxyurea was rapidly absorbed after oral administration with a median time to peak concentration of 0.55 hours (range, 0.467–2.2 hours). Interindividual PK variability of hydroxyurea was substantial; the coefficient of variation was 26.0% for t1/2, 30.3% for Cmax, 46.7% for CL/F, and 61.6% for V/F. Variability in apparent oral clearance was related primarily to patient weight; linear regression indicated R-squared value of 0.533 indicating that over half of the observed interindividual variability could be accounted by weight alone. There was no significant contribution from hepatic or renal function, including glomerular filtration rate. Two distinct PK profiles for hydroxyurea were observed when patients were grouped on the basis of time to peak concentration: rapid and slow absorption phenotypes. For 25 children, the peak hydroxyurea concentration was observed at the first sampling time point, suggesting very rapid absorption; using a linear one-compartment model the predicted median time to peak concentration was 18 minutes. In these patients with the rapid absorption profile, the median Cmax was 74% higher than for the slow absorption (P<0.001) and the median dose-normalized AUC was 33% higher (p=0.037). These novel findings suggest that the rate of absorption of hydroxyurea is an important determinant of systemic exposure and possibly also of pharmacodynamic effects in children with SCA. Studies are ongoing to determine the effect of PK interindividual variation on HbF and LDH responses, as well as hydroxyurea MTD.