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

Russell E Ware1, Jenny M Despotovic, Nicole A Mortier

  • 1International Hematology Center of Excellence, Department of Pediatrics, Baylor College of Medicine, Houston TX, USA. reware@bcm.edu

Blood
|August 31, 2011
PubMed

Insights

Hydroxyurea therapy shows promise for children with sickle cell anemia, but predicting individual responses remains challenging. The HUSTLE study identified factors influencing drug levels and fetal hemoglobin production, yet precise prediction is still elusive.

Area of Science:

  • Pharmacology
  • Genetics
  • Hematology

Background:

  • Hydroxyurea therapy is effective for pediatric sickle cell anemia (SCA).
  • High interpatient variability exists in hydroxyurea's efficacy and maximum tolerated dose (MTD).
  • Accurate predictors for hydroxyurea response in SCA are currently lacking.

Purpose of the Study:

  • To collect first-dose pharmacokinetic (PK) data in pediatric SCA patients starting hydroxyurea.
  • To investigate pharmacodynamic (PD) parameters, including fetal hemoglobin (HbF) response and MTD.
  • To evaluate the influence of pharmacogenetics on PK and PD parameters.

Main Methods:

  • Conducted the HUSTLE study (NCT00305175) involving children with SCA.
  • Collected first-dose PK data from 87 children and PD data from 174 subjects.
  • Analyzed pharmacogenetics, including single nucleotide polymorphisms (SNPs) in genes like BCL11A.

Main Results:

  • Observed significant interpatient variability in PK, identifying rapid and slow oral absorption phenotypes.
  • Confirmed robust PD responses, with %HbF at MTD predicted by baseline %HbF and other variables.
  • Identified serum creatinine as a predictor for MTD, but no genetic factors influenced MTD %HbF or dose.
  • Found SNPs in BCL11A influenced baseline %HbF, but not MTD %HbF or dose.

Conclusions:

  • Hydroxyurea PK and PD exhibit substantial interpatient variability in children with SCA.
  • Predicting hydroxyurea response in SCA remains complex, requiring further research.
  • Pharmacogenetics play a role in baseline HbF but not in MTD response or dose adjustments.

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