Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

• Published in: Blood Vol. 118; no. 18; pp. 4985 - 4991
• Main Authors: Ware, Russell E., Despotovic, Jenny M., Mortier, Nicole A., Flanagan, Jonathan M., He, Jin, Smeltzer, Matthew P., Kimble, Amy C., Aygun, Banu, Wu, Song, Howard, Thad, Sparreboom, Alex
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.11.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Adolescent; Anemia, Sickle Cell - drug therapy; Anemia, Sickle Cell - genetics; Anemias. Hemoglobinopathies; Biological and medical sciences; Biomarkers, Pharmacological - analysis; Biomarkers, Pharmacological - metabolism; Child; Child, Preschool; Clinical Trials and Observations; Diseases of red blood cells; DNA Mutational Analysis; Dose-Response Relationship, Drug; Female; Hematologic and hematopoietic diseases; Humans; Hydroxyurea - administration & dosage; Hydroxyurea - pharmacokinetics; Hydroxyurea - pharmacology; Hydroxyurea - therapeutic use; Male; Maximum Tolerated Dose; Medical sciences; Pharmacogenetics - methods; Polymorphism, Single Nucleotide; Red Cells, Iron, and Erythropoiesis; Human; Antineoplastic agent; Hemoglobinopathy; Pharmacogenetics; Pharmacodynamics; Sickle cell anemia; Hydroxycarbamide; Hematology; Hemopathy; Genetic disease; Hemolytic anemia; Treatment; Antimetabolic; Genetics; Pharmacokinetics; Child
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-364190

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.