Hydroxyurea Pharmacokinetics for Predicting Maximum Tolerated Dose in Children with Sickle Cell Anemia

Background: Hydroxyurea has emerged as the primary disease-modifying therapy for both children and adults with sickle cell anemia (SCA). New guidelines from the National Heart, Lung, and Blood Institute include a recommendation that all children with SCA be offered hydroxyurea as young as nine months of age, regardless of the frequency or severity of clinical complications. The benefits of hydroxyurea are most evident when the dose is escalated to the maximum tolerated dose (MTD); however, a stable MTD may take 8-12 months to achieve. In this era of personalized medicine, individualized pharmacokinetics (PK) profiles can be used to predict appropriate medication dosing. Accordingly, we investigated hydroxyurea PK data in a large cohort of children with SCA at their first oral dose and at MTD, to understand inter-patient variability and to create an accurate dose prediction model for hydroxyurea MTD.

Methods: The Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175) is a longitudinal observational study for children with SCA receiving hydroxyurea therapy. Prospective investigation of hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics is a primary study objective. HUSTLE includes two cohorts of children: a “New Cohort” with children initiating hydroxyurea therapy upon enrollment in the study, and an “Old Cohort” with children already taking hydroxyurea upon study entry. Children in the “New Cohort” received their first oral dose of hydroxyurea 20 mg/kg with formal first-dose PK data collection using peripheral blood analysis at baseline (t=0) followed by 15, 30, 60, 120, 240, and 480 minutes. PK analyses were performed at MTD for both the New and Old Cohorts. Hydroxyurea concentration was determined by a previously described color-based method, testing each sample in triplicate with a standard curve ranging from 0 to 1000mM, and sensitivity as low as 8mM.

Results: A total of 97 children with SCA who enrolled in the New Cohort had first-dose hydroxyurea PK analysis, 65 of whom also had a paired PK study at MTD. Another 34 samples from the Old Cohort had PK analysis performed at MTD.

Baseline (first-dose) hydroxyurea pharmacokinetics revealed substantial interpatient variability, with a coefficient of variation ranging from ~25% for maximum concentration (Cmax) and area-under-the-curve (AUC) to ~50% for time to maximum concentration (Tmax) and apparent oral clearance (CL/F). At MTD, the PK parameters showed an expected increase in Cmax due to the higher average dose, but a convergence toward AUC of ~115 (mg¥hr/mL) with a reduced coefficient of variation. Based on this target AUC, predictive equations were generated that include PK parameters, but the simplest equation for the starting hydroxyurea dose is: Dose (mg) = 400 – [1000 x creatinine] + [21 x weight].

Conclusions: Individual hydroxyurea absorption patterns for young children with SCA can be used to predict MTD. The starting dose can be optimized by using predictive equations that reflect apparent oral clearance instead of body weight alone, and subsequently titrated by marrow suppression. AUC is the most relevant PK parameter, and our data show its variability is consistently lower at MTD, with a target AUC of 115 mg.hr/mL. As the use of hydroxyurea therapy expands, we plan a prospective study to tailor the starting dose using a pharmacometrics model involving weight, renal function, and selected PK parameters to rapidly achieve a safe and stable MTD.