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Clinical Trial
. 2011 Nov 3;118(18):4985-91.
doi: 10.1182/blood-2011-07-364190. Epub 2011 Aug 29.

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

Russell E Ware  1 , Jenny M Despotovic, Nicole A Mortier, Jonathan M Flanagan, Jin He, Matthew P Smeltzer, Amy C Kimble, Banu Aygun, Song Wu, Thad Howard, Alex Sparreboom
Affiliations
Clinical Trial

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

Russell E Ware et al. Blood. .

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.

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Figures

Figure 1
Figure 1
Concentration-time profiles of hydroxyurea in young patients with SCA Shown are representative examples of “Fast” phenotype with peak concentration at 15-30 minutes (59% of patients) and the “Slow” phenotype with Cmax at either 60 or 120 minutes (41% of patients).
Figure 2
Figure 2
Prediction modeling of the hydroxyurea response. (A) The 5-variable model for predicting %HbF response (R2 = 0.48) which is dominated by baseline HbF. (B) The 5-variable model for predicting MTD dose (R2 = 0.35).
See this image and copyright information in PMC

References

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