A Phase 1 Pharmacokinetics (PK) Study of Hydroxyurea (HU) 1,000 mg Coated Breakable Tablets and 500 mg Capsules in Pediatric and Adult Patients with Sickle Cell Disease (SCD).

Controlled studies have shown that HU decreases frequency/severity of painful crises in severe SCD adults/children and reduces the frequency of acute chest syndrome and blood transfusion in adults. There are scarce reports of PK studies (done only with capsules) in SCD adults, and nonexistent in children. Those reports display wide inter-individual and intra-individual variances, complicating the establishment of a proper dosage. Besides, capsules are not well suited for use in children, because it makes very difficult to adapt dosages to body weight.

Aims:

1. to provide adequate PK data on HU tablets in SCD adults and children (HbSS or HbS/β₀ thalassemic) with normal hepatic/renal functions, who were already under HU treatment;

2. to perform an equivalence study of HU pharmacokinetics between capsules and tablets in SCD adults.

We used a standard brand for capsules and we took advantage of a HU 1,000 mg coated-breakable tablet under European regulatory review. Tablets were manufactured according to Good Manufacturing Practice by OTL-Pharma, France.

Methods: Group 1: 11 children (4–19yr) received HU tablets for 14 days (mean dose: 21.4 mg/kg/d, range: 14–36.5); Group 2: 15 adults (21–49yr) were included into a randomised cross-over study comparing tablets to capsules, during two 8-day study periods, separated by 2–4 weeks during which patients received capsules (mean HU dose: 20.8 mg/kg/d, range: 15–35). Blood samples were collected pre-dose, at 0.75, 1.5, 2, 2.5, 3, 4, 6, 24 hours post-dose and urine at 4, 8, 24 hours post-dose. HU was measured by HPLC coupled with an UV detection and PK analysis was carried out by using a non-compartmental WinNonLin software-based method.

Results (mean values): table 1

Conclusion: The main PK parameters were very similar in SCD adults and children, except for the % renal excretion. Renal excretion is similar in SCD children to that reported in adults with cancer, but is twice in SCD adults. This difference might be related to the increase of glomerular filtration rate in SCD adults. Capsules and tablets Cmax, AUC_0–24, AUC_0-∞ and Tmax are equivalent in SCD adults.