463048 Model-Based Novel Strategy for Individualized Treatment of Sickle Cell Disease with Hydroxyurea

Thursday, November 17, 2016: 12:48 PM
Continental 8 (Hilton San Francisco Union Square)
Akancha Pandey1, Robert Hannemann1,2, Terry Vik3, Doraiswami Ramkrishna1 and Sangtae Kim1, (1)School of Chemical Engineering, Purdue University, West Lafayette, IN, (2)Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, (3)Department of Pediatrics, Indiana University, Indianapolis, IN

Sickle Cell Disease is a hereditary disease caused by a single nucleotide mutation in the β subunit of hemoglobin producing abnormal, rigid and sickle shaped red blood cells. Current treatment method involves lifelong treatment with daily oral dosage of hydroxyurea. Hydroxyurea is known to induce fetal hemoglobin synthesis that inhibits hemoglobin polymerization and thus relieves the symptoms associated with the disease. The major side effect of the drug is it inhibits enzyme ribonucleotide reductase, causing bone marrow toxicity.

The main challenges associated with hydroxyurea are substantial interpatient variability in pharmacokinetic and pharmacodynamic profiles, cytotoxicity, non-compliance, lack of an effective biomarker to predict treatment efficacy and consequently lack of optimal dosing regimen for individual patients. Clinical studies have shown that mean cell volume (MCV) of red blood cell (RBC) increases with hydroxyurea treatment and is strongly correlated to treatment outcome. Therefore the MCV of RBC is used as a surrogate marker to monitor treatment progression. However, the effect of the drug on RBC is a manifestation of its effect on the early precursor cells containing nucleus. Red blood cells circulate in the blood for around 120 days and therefore the effect of hydroxyurea can only be seen after such time period. The slower RBC dynamics delays the clinical decision making process. Reticulocyte, an immediate precursor to red blood cell, circulates in blood for a relatively shorter time period before developing into mature red blood cell. Thus, reticulocytes offer faster dynamics and MCV of reticulocytes is proposed in this work as an effective biomarker.

A pharmacodynamic (PD) model is developed to describe reticulocytes dynamics as a function of hydroxyurea dosage. The model uses the population balance approach which uniquely describes the evolutionary distribution of various cell types in the bone marrow and their emergence in the periphery. In order to reduce the myelosuppression and maximize drug efficacy, the drug dosage is optimized based on the response obtained from individual patient pharmacodynamic model. This study shows the feasibility of using MCV of reticulocytes as an effective surrogate biomarker. The model can aid clinicians in timely prediction of individual patient dosage and improve the quality of life among patients. For model validation, the data is collected from Riley Hospital for Children in Indianapolis.


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