Introduction: Hydroxyurea (HU) reduces vaso-occlusive complications, hospitalizations and transfusion requirements in children with sickle cell anemia (SCA; HbSS and HbSβ0thalassemia). Despite linear pharmacokinetics (PK) and apparent dose dependency for HU effect, there remains unexplained large inter-individual variability in drug response. To better understand this variability, we conducted a PK study of HU to assess: 1) effect of multiple dosing on PK of HU, and 2) explore the utility of using a single post-dose HU plasma concentration as a basis for therapeutic drug monitoring.
Methods: Data from two prospective trials, "Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) and "Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease", were utilized for this analysis. Participants were children (≤18 years) with HgbSS and HbSβ0 thalassemia from 8 medical centers in the U.S. One cohort of patients had never been treated with HU and the second cohort had been treated with HU for at least ≥3 months at a stable dose. All participants received a single oral dose of HU and plasma PK samples were collected pre-dose, then at 15, 30, 45, and 60 minutes, and 1.5, 2, 4, 6, and 8 hours after study drug was administered under direct supervision. HU was quantitated from plasma and urine using a validated HPLC method. PK parameters for HU were determined from each patient using a standard model-independent approach (apparent Cmax observed from plasma concentration vs time data; AUC determined via a log-linear approach). PK parameters were compared using parametric (two-sample t-test) or nonparametric (Wilcoxon Rank Sum test) as appropriate based on normality of distribution. The coefficient of determination was used to determine the most predictive relationship between post-peak HU plasma concentrations and systemic exposure (AUC). The significance limit accepted for all statistical analyses was a = 0.05.
Results: A complete plasma HU PK profile was obtained for 59 children. Participants with PK after the first dose (n=7, HUfirst) group received an average dose of 17.9 ±2.6 mg/Kg of HU whereas those with PK after multiple doses (n=52, HUchronic group) received an average dose of 23.8 ±5.1 mg/Kg (p < 0.01). Absorption of HU was rapid in both groups with a time to maximal plasma concentration (Tmax) of 0.9 ±0.58 hours in the HUfirst group and 0.8 ±0.47 hours in the HUchronic group (p=0.68). The mean dose/weight- normalized Cmax in the HUfirst group (2.0 mg/L per 1 mg/kg dose) was 1.4 fold higher than in the HUchronic (1.4 mg/L per 1 mg/kg) (p=0.03). A similar relationship was observed in mean dose/weight-normalized AUCinf, where the HUfirst group was 1.3 fold higher than in the HUchronic group (5.9 vs 4.6 mg/L*hr per 1 mg/kg; p=0.002). Weight-normalized mean apparent oral clearance (Cl/F) was significantly lower in the HUfirst cohort (0.17 L/hr/kg) as compared to the HUchronic (0.23 L/hr/kg) (p<0.001). The mean apparent volume of distribution (Vz/F) for the HUfirst cohort (0.52 L/kg) was not significantly different than that in the HUchronic cohort (0.61 L/kg) (Table 1). As suggested by data in Figure 1a, the apparent mean elimination half-life did not vary between the groups (e.g., 2.1 hr in HUfirst vs. 2.3 hr in HUchronic). Finally, between 45 minutes post-dose and through the last blood sampling point, the 4 hour post-dose concentration most accurately predicted the AUC of HU (r2= 0.78) (Figure 1b).
Conclusion: Weight and dose-normalized PK parameters for HU suggest potential differences in the bioavailability of the drug with multiple dosing. This finding may contribute to the known wide variability in HU response. Finally, a single 4 hour post-dose HU plasma concentration adequately predicts systemic exposure (AUC) to HU and thus, could provide an approach to facilitate dose individualization / optimization.
Liem:National Institute of Health: Research Funding; Ann & Robert H. Lurie Children's Hospital of Chicago: Research Funding; Ann & Robert H. Lurie Children's Hospital of Chicago: Employment. Estepp:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; National Institute of Health: Research Funding.
Asterisk with author names denotes non-ASH members.