The use of hydroxyurea for children and adults with sickle cell anemia (SCA) is increasing, but substantial inter-individual differences exist that limit its utility as a routine and effective therapeutic agent. For example, the drug dosing is highly variable, with the maximum tolerated dose (MTD) for individual patients varying between 10 and 35 mg/kg/day. Some patients develop hematological toxicity at relatively low doses and have a modest HbF response, while others tolerate higher doses with a more robust HbF response. Hematological responses to hydroxyurea therapy vary, with HbF levels at MTD ranging from 5 to >30% even for adherent patients. Therapeutic reduction in hemolysis (lower LDH) is also variable though less well described. Our preliminary data suggest substantial inter-individual differences exist in hydroxyurea pharmacokinetics related to drug absorption and disposition, which could affect the laboratory responses and toxicity profile of hydroxyurea therapy for patients with SCA.
In Specific Aim 1 we will characterize pharmacokinetic phenotypes of hydroxyurea therapy in children with SCA. We hypothesize that there are two distinct pharmacokinetic profiles for hydroxyurea therapy in SCA, based on time to peak absorption. To test this hypothesis, we will prospectively measure first-dose hydroxyurea pharmacokinetics to document the inter-individual variability and identify distinct phenotypes.
In Specific Aim 2 we will investigate the relationships between hydroxyurea pharmacokinetic phenotypes and drug effects. We hypothesize that pharmacokinetic differences can affect the hydroxyurea response, so we will collect prospective pharmacokinetic data from patients with SCA on hydroxyurea therapy whose MTD values have variable % HbF, serum LDH, or MTD values. Distinct response phenotypes for hydroxyurea at MTD have been identified, including high versus low HbF, low MTD, and high LDH despite good HbF induction.
In Specific Aim 3 we will investigate the genetic basis for phenotypic variability in hydroxyurea therapy. We hypothesize that specific genetic differences affect the phenotypes observed with hydroxyurea therapy. To test this hypothesis, we will study candidate genes with predicted involvement in the absorption, transport, and metabolism of hydroxyurea, all of which might affect drug pharmacokinetics. Gene loci involved in the cellular effects of hydroxyurea therapy will also be investigated.
The overall goal of this research proposal is to investigate the pharmacological variability of hydroxyurea therapy in patients with SCA, specifically to understand better the inter-individual differences in dosing, toxicity, and laboratory response. The long-term goal is to use information about the pharmacokinetics, pharmacodynamics, and pharmacogenomics of hydroxyurea therapy to help predict the drug effects for individual patients and ultimately to improve medical care for patients with SCA. ? ? ? ?
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