Mathematical Modeling of Hydroxyurea Therapy in Individuals with Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a chronic hemolytic anemia affecting millions worldwide with acute and chronic clinical manifestations and early mortality. While hydroxyurea (HU) and other treatment strategies managed to ameliorate disease severity, high inter-individual variability in clinical response and a lack of an ability to predict those variations need to be addressed to maximize the clinical efficacy of HU. We developed pharmacokinetics (PK) and pharmacodynamics (PD) models to study the dosing, efficacy, toxicity, and clinical response of HU treatment in more than eighty children with SCD. The clinical PK parameters were used to model the HU plasma concentration for a 24 h period, and the estimated daily average HU plasma concentration was used as an input to our PD models with approximately 1 to 9 years of data connecting drug exposure with drug response. We modeled the biomarkers mean cell volume and fetal hemoglobin to study treatment efficacy. For myelosuppression, we modeled red blood cells and absolute neutrophil count. Our models provided excellent fits for individuals with known or correctly inferred adherence. Our models can be used to determine the optimal dosing regimens and study the effect of non-adherence on HU-treated individuals.

Leveraging mathematical modeling to analyze nonadherence for hydroxyurea therapy in sickle cell disease

“…All participants for HUSTLE provided informed consent, and HUSTLE was approved by the institutional review board at St. Jude Children's Research Hospital. Pharmacy refill records were used to calculate the daily dose (Text S1, Figure S1) 27 from which the daily average drug concentration was calculated using the PK model (Text S2). 27 The mean cell HbF was calculated as shown in Text S2 and was used for modeling and analysis purposes 27 .…”

“…Pharmacy refill records were used to calculate the daily dose (Text S1, Figure S1) 27 from which the daily average drug concentration was calculated using the PK model (Text S2). 27 The mean cell HbF was calculated as shown in Text S2 and was used for modeling and analysis purposes 27 . The models for HU PK, MCV, and HbF originally developed in our previous paper 27 have been described in detail in Text S2.…”

“… 27 The mean cell HbF was calculated as shown in Text S2 and was used for modeling and analysis purposes 27 . The models for HU PK, MCV, and HbF originally developed in our previous paper 27 have been described in detail in Text S2. In this work, the integrated PK‐PD model was extended to study and analyze nonadherence inferred in addition to the missing doses calculated from the pharmacy refill data (see next section).…”

“…In our previous work, we developed computational models to analyze the biomarker profiles for 85 subjects from the HUSTLE clinical trial (NCT00305175; total of 260 participants) and we used the pharmacy refill record to incorporate the nonadherence in the dosing profile 17,27 (Text S1 and S2). In this analysis, we retrospectively analyzed the longitudinal data of 40 subjects that includes hematologic parameters prior to and during HU therapy leaving out participants without sufficient data points or having large time gaps, participants with adherence "adequately" inferred from pharmacy data, and participants receiving blood transfusion for our nonadherence study.…”

“…We used our previously developed model to describe the MCV and HbF dynamics. 27 Using our approach, we estimated the dosing profile of HU treatment based on one biomarker (MCV) and validated the profile using the other (HbF). We also investigated the effect of different dosing profiles on HU treatment.…”