Pharmacokinetics and Safety of Endari (L-glutamine) in Sickle Cell Disease Patients

Study Overview
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Brief Summary
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L-glutamine has been approved in the US to reduce the acute complications of sickle cell disease (SCD) in adult and pediatric patients 5 years of age and older. The purpose of this single-center, open-label, phase 4 study is to evaluate the pharmacokinetic characteristics and safety of L-glutamine in patients with SCD.

Detailed Description
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Sickle cell disease (SCD) is associated with a mutation in the β-hemoglobin gene that results in abnormal polymerization of hemoglobin. Polymerization of hemoglobin causes the red blood cell to sickle, leading to a cascade of events which cause acute complications for SCD patients. L-glutamine has been approved in the US to reduce the acute complications of sickle cell disease (SCD) in adult and pediatric patients 5 years of age and older. The purpose of this single-center, open-label, phase 4 study is to evaluate the pharmacokinetic characteristics and safety of L-glutamine in patients with SCD. 8 SCD patients and 4 healthy volunteers will receive weight-based dosing of L-glutamine for 3 weeks. Doses will be changed weekly: 0.1 g/kg administered twice daily during week 1, 0.3 g/kg administered twice daily during week 2, and 0.6 g/kg administered once daily during week 3. The primary objective is to evaluate the pharmacokinetic characteristics of L-glutamine in SCD patients compared with healthy volunteers.

Official Title
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A Phase 4, Open-Label, Single-Center Study to Assess Pharmacokinetic Characteristics and Safety of Endari in Patients With Sickle Cell Disease

Conditions
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Sickle Cell Disease, Pharmacokinetics

Intervention / Treatment
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* Drug: L-glutamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 5 years of age and older at Screening. Has documented diagnosis of SCD with known genotype (HbSS, HbSβ0 and HbSC). Written informed consent provided by patient or the patient's legally authorized representative. Non-pregnant females of childbearing age must agree to avoid pregnancy during the study and to practice a recognized form of birth control during the course of the study (e.g., barrier, birth control pills, or abstinence). Inclusion Criteria for Healthy Volunteers: No known hematologic illness. No known renal impairment. 18 Years of age or older at screening. Written informed consent provided by patient or the patient's legally authorized representative. African American and Hispanic participants preferred. Exclusion Criteria: Recent significant medical condition that required hospitalization (other than sickle cell crisis) within 2 months prior to starting L-glutamine therapy. History of chronic kidney disease Stage 4 (glomerular filtration rate [GFR]=15-29) or Stage 5 (GFR<15 mL/min/1.73 m2). History of chronic liver disease Child Pugh class C (10-15 points). Received any blood products 3 months prior to starting L-glutamine therapy. Currently pregnant or lactating or planning to conceive during the study period. Currently taking or has taken any form of glutamine supplement within 30 days prior to starting L-glutamine therapy. Has been treated with an investigational medication/treatment within 30 days prior to starting L-glutamine therapy. Is currently enrolled in an investigational drug or device study and/or has participated in such a study within 30 days prior to starting L-glutamine therapy. Factors that would, in the judgment of the investigator, make it difficult for the patient to comply with study requirements. Patient is currently being treated with crizanlizumab or voxelotor. Exclusion Criteria for Healthy Volunteers: Known allergies to L-glutamine. Informed consent document was not completed and signed. Currently pregnant or lactating or planning to conceive during the study period. Known hematologic illness, renal or hepatic impairment. Received any blood products within 3 months of starting L-glutamine therapy.

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-glutamine<br>Pharmacokinetic characteristics of L-glutamine | Drug: L-glutamine<br>* Pharmacokinetic study<br>* Other names: Endari;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients | PK (AUC) | Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose) | 
| Maximum Plasma Concentration (Cmax) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients | PK (Cmax) | Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose) | 
| Half-life (t1/2) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients | PK (t1/2) | Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose) | 
| Time to Peak Concentration (Tmax) of L-glutamine at 0.1 g/kg twice daily, 0.3 g/kg twice daily, and 0.6 g/kg once daily in SCD patients | PK (Tmax) | Week 1 Day 1 (0.1 g/kg dose) and Week 2 Day 1 (0.3 g/kg dose. Week 3 Day 1 and Week4 Day1 (0.6 g/kg once daily dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glutamate levels | Plasma and serum glutamate levels. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 
| Effect of Food on L-glutamine Area Under Curve (AUC) | Food effect on AUC. | Week 1 Day 1, Week 2 Day 1, Week 4 Day 1. | 
| Effect of Food on L-glutamine Maximum Plasma Concentration (Cmax) | Food effect on Cmax. | Week 1 Day 1, Week 2 Day 1, Week 4 Day 1. | 
| L-glutamine Dose Effect on Area Under Curve (AUC) | Dose effect on AUC. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 
| L-glutamine Dose Effect on Maximum Plasma Concentration (Cmax) | Dose effect on Cmax. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 
| L-glutamine Interpatient Variability of Area Under Curve (AUC) | Interpatient variability of AUC. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 
| L-glutamine Interpatient Variability of Maximum Plasma Concentration (Cmax) | Interpatient variability of Cmax. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 
| Ammonia levels | Basal whole blood ammonia levels. | Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, Week 4 Day 1. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell disease, pharmacokinetics, L-glutamine