Population pharmacokinetics and pharmacodynamics analysis of hydroxyurea, in adult patients with sickle cell anemia (SCA), and evaluation of disease markers
Lezzar S. (1), Evene E. (1), Duguet C. (2), Habibi A. (3), Gellen-Dautremer J. (3), Galactéros F. (3), Legrand T. (3) and Hulin A. (3)
(1) PhinC Development, Massy, France, (2) AddMedica, Paris, France, (3) Hôpital Henri Mondor, Créteil, France
Background. Hydroxyurea (hydroxycarbamide) (HU) is an antineoplastic agent, it was approved for indication of sickle cell anemia (SCA), and it acts in reducing the frequency of painful crises. The efficacy of HU in the treatment of SCA is generally attributed to its ability to boost the levels of fetal hemoglobin (HbF). This increasing of HbF% is followed by a decrease of rate of abnormal hemoglobin (HbS) who is responsible of the transformation of the red blood cells from a round shape to a sickle shape and to become rigid and sticky.
Objective. The aim of this study was to characterize the exposure-efficacy relationships between HU and the two disease markers: HbF% and mean corpuscular volume (MCV).
Methods. First, a population pharmacokinetic (popPK) model for HU was established in 120 patients receiving an oral dose (500 – 2000) mg of Hydrea®, once daily for 7 months. Then, the selected popPK model was used in PK-PD modelling, consisting on two independent PK-PD models respectively for HbF% and VCM. Indirect pharmacokinetic-pharmacodynamic (PK-PD) models were tested for both relations since drug impact on each marker was observed after few weeks of treatment.
Results. The popPK model was a 2-compartment parameterized in terms of CL/F, V2/F, Q, V3/F and Ka. For a 70 kg patient, CL/F was 9.87 L/h with a 32% inter- patient CV and the volume of the central compartment was 31.7 L with 80% inter-patient CV. Inter-compartment clearance (Q) was 2.29 L/h, the volume of the peripheral compartment was 73.4 L and constant of absorption Ka was 5.54 h-1.
PK-PD model for HbF% was a model of stimulation of the production of the response parameterized with Emax, EC50, kin and kout. Emax was 17.3%, EC50 was 22.1 mg/L, kin was 0.002 HbF%/day with a 60% inter- patient CV and kout was 0.00047 day-1.
For MCV, the PK-PD model was described by a model of inhibition of the elimination of the response parameterized with IC50, kin and kout. IC50 was 16.8 mg/L with a 71% inter- patient CV, kin was 0.112 MCV (fL)/day with a 10% inter- patient CV and kout 0.0013 day-1.
Conclusion. The observed delay between the blood concentrations and the effect was due to the mechanism of action of hydroxyurea, which acts indirectly on the response. MCV increased more quickly than HbF% and reached a plateau after 3 months while HbF% increase was maintained even after 6 months of treatments. HbF% seems to be a better biomarker than MCV.
