A Population Pharmacokinetic Analysis of L-Glutamine Exposure in Patients with Sickle Cell Disease : Evaluation of Dose and Food Effects
© 2024. The Author(s)..
BACKGROUND AND OBJECTIVE: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants.
METHODS: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed.
RESULTS: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food.
CONCLUSIONS: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits.
CLINICAL TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT04684381).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:63 |
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| Enthalten in: |
Clinical pharmacokinetics - 63(2024), 3 vom: 23. März, Seite 357-365 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sadaf, Alina [VerfasserIn] |
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| Links: |
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| Themen: |
0RH81L854J |
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| Anmerkungen: |
Date Completed 21.03.2024 Date Revised 16.04.2024 published: Print-Electronic ClinicalTrials.gov: NCT04684381 Citation Status MEDLINE |
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| doi: |
10.1007/s40262-024-01349-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a ClinicalTrials.gov: NCT04684381 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND AND OBJECTIVE: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants | ||
| 520 | |a METHODS: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed | ||
| 520 | |a RESULTS: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food | ||
| 520 | |a CONCLUSIONS: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits | ||
| 520 | |a CLINICAL TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT04684381) | ||
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| 700 | 1 | |a Latham, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Kalfa, Theodosia |e verfasserin |4 aut | |
| 700 | 1 | |a Vinks, Alexander A |e verfasserin |4 aut | |
| 700 | 1 | |a Ware, Russell E |e verfasserin |4 aut | |
| 700 | 1 | |a Quinn, Charles T |e verfasserin |4 aut | |
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