title: Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia.
abstract: 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.
authors.affiliation: International Hematology Center of Excellence, Department of Pediatrics, Baylor College of Medicine, Houston TX, USA. reware@bcm.edu
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Despotovic
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mortier
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Flanagan
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Smeltzer
authors.forename: Amy C
authors.initials: AC
authors.lastname: Kimble
authors.forename: Banu
authors.initials: B
authors.lastname: Aygun
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Thad
authors.initials: T
authors.lastname: Howard
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide
chemical_list: D054316:Biomarkers, Pharmacological; D006918:Hydroxyurea