Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach

Abstract

Background: Hydroxyurea (HU) is a FDA- and EMA-approved drug that earned an important place in the treatment of patients with severe sickle cell anemia (SCA) by showing its efficacy in many studies. This medication is still underused due to fears of physicians and families and must be optimized. Methods: We analyzed our population and identified HU pharmacokinetic (PK) parameters in order to adapt treatment in the future. Working with a pediatric population, we searched for the most indicative sampling time to reduce the number of samples needed. Results: Nine children treated by HU for severe SCA were included for this PK study. HU quantification was made using a validated gas chromatography/mass spectrometry (GC/MS) method. Biological parameters (of effectiveness and compliance) and clinical data were collected. None of the nine children reached the therapeutic target defined by Dong et al. as an area under the curve (AUC) = 115 h.mg/L; four patients were suspected to be non-compliant. Only two patients had an HbF over 20%. The 2 h sample was predictive of the medication exposure (r2 = 0.887). Conclusions: It is urgent to be more efficient in the treatment of SCA, and pharmacokinetics can be an important asset in SCA patients.

Tolerability and age‐dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats

“…Using pharmacokinetic data from a clinical study, an AUC of 115 μg * h/ml has been proposed as a target AUC for the initial HU dose in children (Dong, McGann, Mizuno, Ware, & Vinks, 2016). In children given an average of 20 mg/kg daily, the AUC of HU ranged from 68 to 116 μg * h/ml (Estepp et al, 2016; Nazon et al, 2019). In our study, young rats administered 75 mg/kg/day had AUC values of 41–86 μg * h/ml, which approximates the AUC value observed in children.…”

Drug Therapies for the Management of Sickle Cell Disease

“…Hydroxyurea further ameliorates SCD morbidity by decreasing the risk of stroke and chronic kidney disease 44 , 45 and may reduce mortality in SCD 46 – 49 . Recent studies to optimize hydroxyurea therapy are exploring dose maximization via pharmacokinetics-based dosing 50 – 54 . Despite its multiple benefits, a substantial number of patients on hydroxyurea may not obtain an adequate clinical response.…”

How Hydroxyurea Alters the Gut Microbiome: A Longitudinal Study Involving Angolan Children with Sickle Cell Anemia

“…Sickle cell anemia (SCA) is one of the most common inherited monogenic diseases in the world, affecting more than 300,000 newborns annually [ 1 ]. It is estimated that 50–90% of SCA infants born in Sub-Saharan Africa, where the disease is most prevalent, die before the age of 5 years [ 2 ].…”

“…The carriers of the sickle cell trait (HbAS) are often asymptomatic, whereas homozygotes (HbSS) suffer from SCA, which is the most severe form of sickle cell disease (SCD) [ 5 , 6 ]. These patients have a lifelong disorder mainly characterized by chronic hemolytic anemia, vaso-occlusive crisis (VOC), strokes, pulmonary hypertension, and bacterial susceptibility that can lead to septicemia [ 1 , 2 , 4 ]. However, infants typically only start to experience SCA symptoms after 6 months of age, when HbF levels begin to decrease [ 7 ].…”

“…Until very recently, hydroxyurea (HU) was the only FDA- and EMA-approved drug for the treatment of patients with SCA [ 1 ]. It is considered a ribonucleotide reductase inhibitor that, when administered once daily at the correct dose (normally 15–30 mg/kg), increases fetal hemoglobin levels (HbF); however, its magnitude of response is very variable [ 8 , 9 ].…”