M. Dong, M. E. Mpollo, P. Malik, A. A. Vinks; Cincinnati Children's Hospital Medical Center, Cincinnati, OH

BACKGROUND: Zileution (ZL) is a derivative of hydroxyurea that may provide significant benefit for patients with sickle cell disease (SCD). The pharmacokinetics (PK) and pharmacodynamics (PD) of ZL were evaluated in pediatric and adult SCD patients as part of a phase I study. Model simulation was performed to support dose selection for future clinical trials.
METHODS: Plasma concentrations from nine patients (age 16.8 ± 7.0 year; weight 79.2 ± 24.1 kg) were available for PK analysis. A Bayesian approach with a ZL population model adapted from the literature (the prior) was used for the analysis (software package MW/Pharm). PK data were also analyzed by non-linear mixed effect modeling (NONMEM 7.2). Covariate effects of body weight and age on ZL PK were explored by linear regression. Correlation of ZL PK parameters including the area under the concentration-time curve (AUC) and pre-dose concentration (Ctrough) with the PD indices (methacholine challenges test [MCT]) were examined. For dose selection, five dosing scenarios were simulated for a hypothetical pediatric population and PK endpoints (AUC and Ctrough) at steady state were used for the evaluation.
RESULTS: MW/Pharm and NONMEM provided consistent estimation of the primary PK parameters (CL/F and V/F). Regression analyses showed that body weight but not age was associated with ZL PK. No clear association between exposure and MCT was identified due to small sample size. Model simulations showed that the target ZL exposures could be achieved by titrating ZL doses based on patients’ body weight.
CONCLUSION: Future large scale studies would be needed to confirm the predicted ZL doses and to improve understanding of the association between ZL exposure and clinical outcome in SCD patients.