A Population Pharmacokinetic Analysis of l-Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects

Abstract

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).