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

Evaluation of the Impact of Renal Function on the Pharmacokinetics of Hydroxyurea (SIKLOS ®) in Normal-renal Function, Hyperfiltrating and Renal Failure Sickle Cell Disease Patients (DARH)

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Renal Function Disorder
• Intervention / Treatment: Drug: Siklos

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Creteil, France
    • Centre de Référence des Syndromes Drépanocytaires Majeurs, Hôpital Henri-Mondor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal-renal function; Normal-renal function: 90 ≤ GFR ≤ 130 mL/min/1.73m2 in women or 140 mL/min/1.73m2 in men	Drug: Siklos; Other Names: hydroxyurea
Experimental: Glomerular hyperfiltration; Glomerular renal hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140 mL/min/1.73m2 in men.	Drug: Siklos; Other Names: hydroxyurea
Experimental: Moderate renal failure; Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2	Drug: Siklos; Other Names: hydroxyurea

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: ADDMEDICA SASA
• Investigators: Principal Investigator: BARTOLUCCI Pablo, MD, Centre de Référence des Syndromes Drépanocytaires Majeurs, Hôpital Henri-Mondor

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 28, 2016

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: August 11, 2015
• First Posted (Estimate): August 13, 2015

Study Record Updates

• Last Update Posted (Actual): October 12, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics of Hydroxyurea
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: SIK-FR 14-1