Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen View Full Text


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Article Info

DATE

2011-05-28

AUTHORS

Ines Paule, Hind Sassi, Anoosha Habibi, Kim PD Pham, Dora Bachir, Frédéric Galactéros, Pascal Girard, Anne Hulin, Michel Tod

ABSTRACT

BackgroundHydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment.MethodsThe models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months.ResultsThe PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients.ConclusionsThe high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU.Trial RegistrationThe clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient. More... »

PAGES

30

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1750-1172-6-30

DOI

http://dx.doi.org/10.1186/1750-1172-6-30

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015504519

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21619673


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25 schema:description BackgroundHydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment.MethodsThe models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months.ResultsThe PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients.ConclusionsThe high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU.Trial RegistrationThe clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient.
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32 Ethics Committee
33 France
34 HU
35 HU exposure
36 HU treatment
37 MCV
38 MethodsThe model
39 NONMEM VII
40 PK
41 PK profiles
42 adult patients
43 anemia
44 anemia patients
45 approach
46 arm
47 basis
48 bicompartmental model
49 biomarkers
50 cell anemia
51 central volume
52 clearance
53 clinical studies
54 comparison
55 consent
56 continuous dosing
57 corpuscular volume
58 cv
59 data
60 days
61 different dosing regimens
62 dosing
63 dosing regimens
64 drug exposure
65 dynamics
66 effect
67 effect of HU
68 elimination
69 exposure
70 exposure-efficacy relationship
71 fetal hemoglobin percentage
72 good biomarker
73 hemoglobin percentage
74 high variability
75 hydroxyurea
76 informed consent
77 inhibition
78 inhibition of elimination
79 levels
80 local ethics committee
81 maximum
82 median
83 median value
84 model
85 modelling approach
86 month 26
87 month 3
88 months
89 objective
90 order
91 part
92 patients
93 percentage
94 pharmacodynamics
95 pharmacokinetics
96 pharmacological treatment
97 population
98 population pharmacokinetics
99 profile
100 range
101 recommendations
102 regimen
103 regimens
104 relationship
105 response
106 sequential modelling approach
107 sickle cell anemia
108 sickle cell anemia patients
109 simulation-based techniques
110 simulations
111 steady-state levels
112 steady-state value
113 strong response
114 studied range
115 study
116 technique
117 terms
118 time
119 treatment
120 turnover model
121 values
122 variability
123 volume
124 work
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