Evaluation of the Impact of Renal Function on the Pharmacokinetics of SIKLOS ® (DARH)

Phase 4

Completed

Conditions: Sickle Cell Disease
Renal Function Disorder

Interventions: Drug: Siklos

Registration Number: NCT02522104

Lead Sponsor: Theravia

Brief Summary: The use of hydroxyurea in sickle cell disease patients with glomerular hyperfiltration and renal failure requires a specific monitoring and dose adjustment in order to remain within the therapeutic interval while limiting the risk of toxicity or therapeutic failure. For this reason the investigators propose to compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Age ≥ 18 years.
Male or female.
Sickle cell disease (SS or S-β0thal) confirmed by haemoglobin electrophoresis and genotyping by deoxyribonucleic acid (DNA) analysis.
Affiliation to a social security system.
Having freely consented in writing after being informed of the objective, programme and potential risks incurred.

These criteria will apply to the 3 groups of sickle cell disease patients according to the renal function stage defined by the glomerular filtration rate (GFR) estimated by the formula of the Chronic Kidney Disease EPIdemiology (CKD EPI) collaboration without ethnic criterion during the last 6 months before inclusion:

Normal-renal function: 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men.
Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2.
Glomerular renal hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140 mL/min/1.73m2 in men.
- Treated with hydroxyurea (Siklos®) with a stable dosage for at least one week ± 2 days before inclusion in the study and dose administered in the morning at 9:00 ± 15 minutes.

Exclusion Criteria

Refusal to consent.
Patients that do not comply.
Occurrence of vaso-occlusive crisis in the month prior to the inclusion in the study.
Patients having had an exchange transfusion in the 15 days before inclusion in the study.
Patients participating in another clinical trial or in the exclusion period of a previous clinical trial.
Patients treated with a diuretic.
Dialysis patient.
Patients with an intercurrent disorder, especially inflammatory, that has not recovered for at least one month.
Pregnant or breast-feeding women.
Patients deprived of liberty or under legal protection.
Patients who cannot understand the objective and the course of the study, incapable of giving their consent.
In the event of severe hepatic failure.
In the event of severe renal failure (creatinine clearance < 30 ml/min).
Patients who show toxic signs of bone marrow suppression.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Normal-renal function	Siklos	Normal-renal function: 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men
Glomerular hyperfiltration	Siklos	Glomerular renal hyperfiltration: GFR \> 130 mL/min/1.73m2 in women and GFR \> 140 mL/min/1.73m2 in men.
Moderate renal failure	Siklos	Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2

Primary Outcome Measures

Name	Time	Method
Measure of Plasmatic Data: Maximum Concentration (Cmax)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Minimum Concentration (Cmin)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Elimination Half-life (T½)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Total Clearance (Cl Tot)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Time to Obtain the Maximum Concentration (Tmax)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Area Under the Curve (AUC0-24)	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Plasmatic Data: Distribution Volume	0 hour, 0.75 hour, 1.5 hours, 3 hours, 4 hours, 6 hours, 7.5 hours , 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Urinary Data: Hydroxyurea Urinary Fractions	From 0 to 4 hours, 4 to 7.5 hours and 7.5 to 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure
Measure of Urinary Data: Renal Clearance (Cl Renal).	From 0 to 4 hours, 4 to 7.5 hours and 7.5 to 24 hours	Compare the pharmacokinetic parameters of hydroxyurea in normal-renal function sickle cell patients to those of patients with glomerular hyperfiltration or moderate renal failure