Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia

Abstract

Aims: Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA.

Methods: Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD.

Results: PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1) h.

Conclusion: We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly.

Keywords: cystatin C; hydroxyurea (HU); individualized dosing; maximum tolerated dose (MTD); population pharmacokinetics; sickle cell anaemia (SCA).

Figure 1

The distributions of AUC(0,∞) at day 1 (A) and at the MTD (B). The red dashed lines represent 10^th, 50^th and 90^th percentile of the data

Figure 2

Goodness‐of‐fit plots for the final PK model. (A) Population prediction vs. observed concentration. (B) Individual prediction vs. observed concentration. (C) Conditional weighted residuals (CWRES) vs. population prediction. (D) Conditional weighted residuals (CWRES) vs. time after dose. Dashed red line, a locally weighted least‐squares regression; solid black line, line of identity

Figure 3

Prediction‐corrected visual predictive check (pcVPC) of the final model. Open circles, observed plasma concentration; dashed red lines, lower (2.5^th) and upper (97.5^th) percentiles of the observed data; solid red line, 50^th percentile of the observed data; black lines, simulated prediction intervals at 5^th, 50^th and 95^th percentiles; shaded areas, confident interval about the prediction intervals in each bin

Figure 4

Model predicted hydroxyurea PK profiles (A) and AUCs (B) with various cystatin C concentrations in a typical paediatric patient. , Cystatin C = 0.50 mg l⁻¹; , Cystatin C = 0.75 mg l⁻¹; , Cystatin C = 1.25 mg l⁻¹; , Cystatin C = 2.0 mg l⁻¹

Figure 5

Correlation between AUC(0,∞) estimated by a one compartment model and by the trapezoidal rule