Impact of renal function on hydroxyurea exposure in sickle‐cell disease patients

Abstract

This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics.Methods: We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated highperformance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR.Results: The HU PK model was constructed as a 2-compartment model with firstorder absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed. Conclusion:Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease.

Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study

“…Secondly, clinician should not hesitate to increase the dose of HU (data not collected here) up to the maximum tolerated dose (neutrophils target around 2000/mm 3 ) in those patients with high risk of mortality. Nevertheless, evidence regarding the “maximum tolerated dose” regimen in adults is poor and depends on the patient's renal function, 15 but well demonstrated in children. 16 , 17 If this strategy fails, exchange transfusion programs or bone marrow transplantation may be proposed.…”

Spotlight Commentary – Voxelotor: A new kid on the block in the treatment of sickle cell disease

“…As alterations in renal function may occur in SCD, the impact of renal function on hydroxycarbamide exposure in SCD patients was recently evaluated by Pressiat and colleagues in the British Journal of Clinical Pharmacology 3 . The PK results of this study showed that systemic exposure to hydroxycarbamide is correlated with renal function, and patients with a high estimated glomerular filtration rate (eGFR) presented a higher renal clearance of hydroxycarbamide, resulting in a need for higher doses.…”